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RDC RESOLUTION NBR 17, OF APRIL 16, 2010

Provides for the Good Manufacturing Practices for Medicinal Products.


The Steering Committee of the National Health Surveillance Company (ANVISA), in the use
of its attributions granted in the section IV of the article 11 of the regulation approved by the Decree
nbr. 3.029, of April 16, 1999, and in view of the provision in the section II and in the paragraphs 1st
and 3rd of the article 54 of the Internal Regiment approved as per the terms of the Schedule I of the
Directive nbr 354 of ANVISA, of August 11, 2006, republished in the Official Gazette of August
21, 2006 in a meeting carried out on April 12, 2010,
adopts the following Resolution of the Steering Committee and I, Executive Director, order its
publication:
TITLE I
INITIAL PROVISIONS
CHAPTER I
OBJECTIVE
Article 1st. This resolution aims at establishing the minimum requirements to be followed in the
production of medications to standardize the verification process of the fulfillment of the Good
Manufacturing Practices for Medicinal Products (GMP) for human use during sanitation
inspections.
1st It is incorporated the GMC Resolution nbr 15/09 - "Good Manufacturing Practices for
Pharmaceutical Products and Implementation Mechanisms within the scope of the MERCOSUL",
which sets forth the adoption of the Report nbr. 37 issued by the WHO (WHO Technical Report
Series 908), published in 2003.
2nd It can be adopted alternative actions to those described in this resolution in order to follow the
technological advance or to consider the specific needs of a determined medication, since they are
validated by the manufacturer and that the quality of the medication is assured.
CHAPTER II
SCOPE
Article 2nd The establishments that produce medications shall fulfill the guidelines of this
resolution in all operations involved in the production of medications, including medications under
development destined to clinical essays.
Sole Paragraph. The activities related to the substances subject to special control, medications that
contain it, shall follow the provisions of the specific law, besides the requirements contained in this
resolution.
Article 3rd The medications registered shall only be produced by companies dully licensed to this
activity, which shall be regularly inspected by the national competent authorities.

Article 4th This resolution shall include all the aspects of occupational safety and environmental
protection, which shall be ruled by specific legislation.
Sole Paragraph. The manufacturer shall guarantee the safety of employees and shall take the
necessary steps for the environment protection.
CHAPTER III
DEFINITIONS
Article 5th By this resolution, it shall be adopted the following definitions:
I corrective action; a corrective action shall eliminate the cause of a non-compliance detected, or
any other undesirable situation;

II preventive action: action adopted to eliminate the cause of a potential non-compliance or any
other undesirable situation;

III Adjustment: operation destined to make a measurement instrument to have performance


consistent with its use;

IV reference samples:

samples of raw materials and finished products maintained by the


manufacturer, dully identified, for a determined time. The amount of sample shall have at least the
double of the amount necessary to effect all the analysis scheduled;

V - representative sample: - the amount of sample statistically calculated, representative of the


sampled universe, taken for analysis purposes for the liberation of a batch of the material or
product;

VI prechamber: closed room with two or more doors, interposed among two or more areas of
classes of distinct cleaning, aiming at controlling air flow between both, when they need to be got
in. The prechamber is projected so that it can be used by people, materials or equipment;

VII area: limited physical room, where operations are carried out under specific environmental
conditions;

VIII cleaned area: area with environmental control regarding contamination with feasible and
non-feasible particles, projected, built and used in a way to reduce introduction, generation and
retention of contaminants inside it;
IX - segregated area: installations that offer complete and total separation of all the aspects of an
operation, including personnel and equipment movement, with well-established procedures,
controls and monitoring. It can include physical barriers and separated air systems as well, but it
does not necessarily imply in distinct buildings;
X - calibration: a set of operations that established, under specific conditions, the relationship
between the values indicated by a measurement instrument or systems or the values represented by

a materialized measure or a reference measure, and the values corresponding to the magnitudes
established by patterns;

XI - contamination: the non-desired introduction of impurities of chemical and microbiological


nature, or of strange material, in raw material, intermediate product and/or finished product during
the steps of sampling, production, packaging or repackaging, storing or transporting;

XII

cross contamination: contamination of a determined raw material, intermediate product,


bulk product or product finished by other raw material, during the production process;
XIII control in process: inspections carried out during the production in order to monitor and, if
necessary, to adjust the process in order to guarantee the product is kept as per its specifications.
The environment control, or the equipments, may also be considered as part of the control in
process;

XIV - acceptance criteria: a criterion that sets forth the acceptance limits of the raw materials,
products or processes/systems specifications;
XV Expiration date: date determined in the medications packing (usually in labels) which is
expected the product is within the specifications, provided they are correctly packed. This date is
determined by batch, summing up the expiration date;
XVI - retest date: date established by the input manufacturer, based on stability studies,
after which the material shall be reanalyzed in order to guarantee that it is still suitable for the
immediate use, as per indicative tests of stability defined by the input manufacturer and keep the
pre-established conditions of storage. Retest date is only applicable when the validity term has not
been established by the input manufacturer;

XVII - vegetable drugs by-products: extract, tincture, oil, wax, exudate and the like;
XVIII - quality deviation: dismissal of the quality parameters established for a product or a process:
XIX - batch documentation: all the documents associated to the manufacture of a batch of a bulk
product or finished product. It provides for a history on each product batch and all the
circumstances pertaining to the quality of the final product;

XX - vegetable drug: medicinal plant, or its parts, which contain the substances, or classes of
substances, responsible for the therapeutic action, after procedures of collection, stabilization and/or
drying, and it can be integral, erased, grinded or pulverized;

XXI Packaging: all operations, including tuning and labeling, through which bulk product shall
pass in order to become a finished product. Usually, tuning of sterile products is not considered part
of the packing process, since it is considered as bulk product in its primary packing;

XXII - Specification: a document that describes in details the requirements the materials used
during manufacture, intermediate products and finished products shall fulfill. Specifications serve
as basis for quality evaluation;

XXIII - Manufacture: all operations involved in the preparation of a determined medication,


including the acquisition of materials, production, quality control, liberation, storage,
commissioning of finished products and the related controls;
XXIV Manufacturer: holder of the Operation License for production of medications issued by the
competent authority of the Ministry of Health, as per set forth in the sanitation legislation in effect;
XXV - Master formula/standard formula: document or group of documents that specify the raw
materials and the packing materials with their respective amounts, together with the description of
the procedures and necessary precautions for the production of a determined amount of the finished
product. In addition, it provides for instructions on processing, including on controls in process;

XXVI Active pharmaceutical input: any substance introduced in the formulation of a


pharmaceutical form, when used in a patient, acts as an active ingredient. Such substances may have
a pharmacological activity, or other direct effect in the diagnosis, heal, treatment or prevention of a
disease, and it may affect the structure and working of the human organism;
XXVII facilities: physical room limited with machines, arrangement, equipment and auxiliary
systems used for the execution of processes;
XXVIII batch: set amount of raw material, packing material or product processed in one or more
processes, whose essential feature is homogeneity. At times it may be necessary to divide a batch
into sub-batches, which shall be grouped to form a homogeneous final batch. In a continuous
production, a batch shall correspond to a defined part of the production, characterized by
homogeneity;

XXIX marker: composed or class of chemical compounds (i.e: alkaloid, flavonoids, fatty acids,
etc.), present in the vegetable raw material, preferably related to the therapeutical effect, which is
used as a reference in the quality control of the vegetable raw material and of the phytotherapics;
XXX - packing material: any material that, including printed material, is employed in a
medication packing. Its excluded from this definition other packing used for transport or
commissioning. Packing materials are classified as primary or secondary, as per the degree of
contact with the product;

XXXI - raw material: any substance, whether active or not, with defined specification, used in the
medications production. Packing materials are excluded from this definition;
XXXII vegetable raw material: fresh medicinal plant, vegetable drug or by-product of a vegetable
drug;

XXXIII medication: pharmaceutical product, technically obtained or elaborated, with


prophylactic, curative, palliative or for diagnostics purpose;

XXXIV - phytotherapics: medication obtained with the exclusive employment of vegetable active
raw materials. Its characterized by the knowledge of the efficiency and the risks of its use, as well
as by the reproducibility and faithfulness of its quality. Its efficiency and safety are validated by
etnopharcacological data, of usage, technical and scientifical documents and clinical evidences. Its
not considered a phitotherapics medication the one that, in its composition, includes isolated active
substances, of any origin, neither the association of these with vegetable extracts;

XXXV - botanical nomenclature: gender and species;


XXXVI complete official botanical nomenclature: gender, species, variety, binominal author and
family;
XXXVII batch number: combination defined by numbers and/or letters that identify, in a unique
form, a batch in their labels, batch documents, corresponding analysis certificates, among others;
XXXVIII critical operation: operation in the manufacturing process that may affect the
medication quality;
XXXIX production order: document or set of documents that serve as a basis for the batch
documentation. It shall be filled in with data obtained during production and that includes
information of the master formula/standard formula;
XL appointed person: qualified professional appointed by a company for the execution of a given
activity;
XLI Worst case: one or more conditions that present the major possibilities of defect of a product
or of the procedure when it comes to ideal conditions. Such conditions not necessarily imply in
deviations in the product or procedure;
XLII Master Plan of Validation (PMV): general document that sets forth strategies and guidelines
for validations adopted by the manufacturer. It provides for information on the work program of
validation, sets forth details, responsibilities and a schedule for the work to be done;
XLIII reference standard: it is example of pharmaceutical, impurities, decay products, reagents,
among others, highly characterized and of highest purity, whose value is accepted with no reference
to other standards;
XLIV secondary standard (working standard): standard used in the laboratory routine, whose
value is established by a comparison to a reference standard;
XLV Standard Operational Procedure (POP): written and authorized procedure that provides for
instructions for operations not necessarily specific to a given product or material, but of general
nature (for instance, operation, maintenance and cleaning of equipment; validation; cleaning of the
facilities and environmental control; sampling and inspection). Some procedures may be used to
supplement the master document of batch production of a specific product;

XLVI production: all operations involved in the preparation of a determined medication, from the
receipt of the materials in the warehouse, passing through the processing and packing, up to the
obtainment of a finished product;
XLVII bulk product: any product that has passed through the steps of production, not including
packing procedure. Sterile products in their primary packing shall be considered bulk product;
XLVIII returned product: finished, dispatched and commercialized product returned to the
manufacturer;
XLIX intermediate product: product partially processed that shall be submitted to subsequent
steps of production before becoming a bulk product;
L finished product: product that has passed through all the steps of production, including labeling
and final packing;
LI Validation Protocol (or Plan) (PV): document that describes the activities to be carried out in
the validation of an specific product, including schedule, responsibilities and acceptance criteria for
the approval of a productive process, cleaning procedure, analytical method, computer system or
part of these for routine use;
LII qualification: set of actions done to attest or document that any facilities, systems and
equipment are properly installed and/or work correctly and lead to the expected results.
Qualification is usually a part of the validation, but the individual steps of qualification do not
constitute solely a procedure validation;
LIII Performance Qualification (QD): documented verification that the equipment or system
presents a consistent and reproducible performance, as per a set of parameters and specifications,
for long periods. In some cases, it may also be used the term procedure validation;
LIV Installation Qualification (QI): a set of operations carried out to assure the facilities (such as
equipment, infra-structure, measurement instruments, utilities and production area) used in the
productive processes and/or in the computer systems are suitably selected and correctly installed as
per the established specifications;
LV Operation Qualification (QO): a set of operations that sets forth, under specific conditions,
that the system and the subsystem operates as per the expected, in all the operational areas
considered. All the equipment used in the execution of tests shall be identified and ruled before they
are used;
LVI Project Qualification (QP): documented evidence that the installations, support systems,
utilities, equipment and procedures have been designed as per the GMP requirements:
LVII quarantine: temporary retention of raw materials, packing materials, intermediate products,
in bulk or finished. These shall be kept physically isolated - or by other efficient means, while
awaiting for a decision on the liberation, rejection or reprocessing;

LVIII reanalysis: analysis carried out in the raw material, previously analyzed and approved, to
confirm the maintenance of the specifications set by the manufacturer, within its validation term;
LIX reconciliation: comparison between the theoretical and the current amounts in the different
steps of production of a product batch;
LX recovery: total or partial incorporation of the previous batches of proven quality to another
batch, in a determined step of production;
LXI - Validation Report (RV): document in which the registries, results and evaluation of a
validation program shall be consolidated and summarized. It may also contain improvement
proposals;
LXII remittance or delivery: amount of a determined material supplied as per a purchase order. A
sole remittance may include one or more volumes and materials belonging to more than one batch;
LXIII reprocedure: repetition of one or more steps that are already part of a manufacturing
process established in a batch that is not compliant to the specifications;
LXIV technical responsible: person accredited by the national ruling authority with the
responsibility of assuring that each product batch has been manufactured, tested and approved for
liberation, according to the laws and rules in effect in the country;
LXV revalidation: partial or total repetition of the validations of procedure, cleaning or the
analytical method in order to assure that these are fulfilling the requirements established;
LXVI computer systems: large scale systems including, but not limited to, automated equipment
of production, automated laboratory equipment, process control, analytical control, production
execution, management of laboratory information, planning of production resources and
management and monitoring system of documents. A computer system is formed by hardware,
software and net components, summed up to the controlled functions and related documents;
LXVII High Volume Parental Solution (SPGV): sterile and apyrogenic solution, destined to the
parental application in a unique dose, whose volume is of 100mL or upper. It is included in this
definition solutions for irrigation and solutions for peritoneal dialysis;
LXVIII validation: documented act that attest that any procedure, process, equipment, material,
activity or system really and consistently leads to the expected results;
LXIX concurrent validation: validation carried out during the production routine of products
destined to sale;
LXX cleaning validation: documented evidence that shows that cleaning procedures remove
residuals to pre-determined levels of acceptance, taking into consideration factors such as batch
size, dose, toxicological data, solubility and contact area of the equipment with the product;

LXXI process validation (VP): documented evidence that attests, with a high degree of safety, that
an specific process will produce a product in a consistent form, which accomplishes with predefined specifications and quality characteristics;
LXXII validation of computer systems: documented evidence that attests, with high degree of
safety, that an analysis of a computer system, controls and registries are correctly done and that data
processing fulfills the pre-determined specifications;
LXXIII prospective validation: validation done during the product development step, based in a
risk analysis of the productive process, which is detailed in individual steps; these, at their turn,
shall be evaluated based on experiences to determine if they can cause critical situations; and
LXXIV retrospective validation: it involves evaluation of the past experience of production, under
the condition that composition, procedures and equipment are unaltered.
TITLE II
QUALITY MANAGEMENT IN THE MEDICATIONS
INDUSTRY: PHILOSOPHY AND ESSENTIAL
ELEMENTS
Article 6th Quality management decides on the implementation of the Quality Policy, i.e., the
intentions and global guidelines regarding quality, formally expressed and authorized by the higher
management of the company.
Article 7th The basic elements of quality management shall be:
I - suitable infrastructure or quality system, including facilities, procedures, processes and
organizational resources; and
II systematic actions necessary to assure, with suitable confidence, that a product (or service)
fulfills its quality requirements. The totality of these actions is called quality assurance.
Article 8th Within an organization, quality assurance is used as a management tool. In contract
situations, quality assurance also serves to manage confidence of its suppliers.
Article 9th Concepts of quality assurance, GMP and quality control shall be interrelated and
addressed in the quality management. They are described in this resolution in a way that it is
emphasized their relationships and importance to medications production.
CHAPTER I
QUALITY ASSURANCE
Article 10. Quality assurance is a wide concept and shall include all the aspects that individually
or collectively influence the quality of a product.
1st It addresses the totality of the provisions adopted aiming at assuring that medications are
within the quality standards required, so that they can be used for the proposed purposes.

2nd Quality Assurance includes GMP and other factors, including the project and development
of a product, which are not included in the purposes of this resolution.
Article 11. The system of quality assurance suitable to medications production shall assure:
I medications are planned and developed in a way it is considered the GMP and other
requirements, such as good practices of laboratory (BPL) and clinical good practices (BPC);

II production and control operations are clearly specified in a document formally approved and
the GMP requirements are fulfilled;
III management responsibilities are clearly specified in the positions descriptions;
IV - provisions are taken for the production, distribution and the correct use of raw materials and
packing materials;
V - it is carried out all the necessary controls regarding raw materials, intermediate products and
bulk products, as well as other controls in procedures, calibrations and validations;
VI the finished product is correctly processed and verified according to given procedures;

VII medications are not commercialized or distributed before the responsibles have assured that
each production batch is produced and controlled as per the registry requirements and any other
norms relevant to production, to the control and to the release of medications;
VIII it is supplied instructions and taken the necessary provisions to assure that medications are
warehoused by the manufacturer, distributed and subsequently handled, in a way that quality is kept
along the validation term;
IX there is a self-inspection procedure and/or an internal quality auditing that regularly evaluates
the effectiveness and applicability of the system of quality assurance;
X deviations are reported, investigated and logged;
XI there is a control system of changes; and
XII it is carried out regular evaluations in the quality of medications, aiming at verifying the
consistency of the process and assuring its continuous improvement.
Article 12. The manufacturer is responsible for the quality of the medications produced, assuring
they are suitable for its purposes, fulfill the requirements set forth in its registry and do not put
patients in risk due to unsuitable safety, quality or efficiency.
1st The fulfillment of this objective is the responsibility of the company higher management and
this requires the participation and commitment of employees in all company levels, of the
contractors and of distributors.

2nd In order the objective is reached in a trusty manner, there shall be a system of Quality
Assurance totally structured and correctly implemented that incorporates the GMPs.
3rd The system of Quality Assurance shall be totally documented and shall have its effectiveness
monitored.
4th All the parts of the system of Quality Assurance shall figure on competent and qualified
personnel, besides having enough and suitable room, equipment and installations.
CHAPTER II
GOOD MANUFACTURING PRACTICES FOR MEDICINAL PRODUCTS (GMP)
Article 13. Good Manufacturing Practices is part of the Quality Assurance that assures the products
are consistently produced and controlled, with suitable quality standards for the intended use and
required by the registry.
1st The fulfillment of this GMP is firstly oriented for the decrease of the risks inherent to any
pharmaceutical production, which cannot be detected only by the realization of trials in the finished
products.
2nd Risks are essentially constituted by cross-contamination, contamination by particles, exchange
or intermingling of a product.
3rd The GMPs set forth that:

I - all the manufacturing processes shall be clearly defined and systematically revised due to the
experience obtained. - Moreover, they shall be able to produce medications within the quality
standards required, fulfilling the respective specifications;
II it is carried out the necessary qualifications and validations;
III all the necessary resources are supplied, including:
a) qualified and dully trained personnel;
b) Suitable and identified facilities and installations;
c) Equipment, computer systems and suitable services;
d) appropriate materials, recipients and labels;
e) Approved and effective procedures and instructions;

f) Suitable warehousing and transportation; and

g) Installations, equipment and qualified personnel for control in process.


IV the instructions and procedures are written in a clear and unequivocal language, and are
applicable in a specific manner to the facilities used;
V workers shall be trained to correctly perform the procedures;

VI it shall be made logs (manually and/or through log instruments) during the production to
demonstrate that all steps contained in the procedures and instructions have been followed and that
the amount and the quality of the product obtained are in compliance with the expectations. Any
significant deviations shall be logged and investigated;
VII the registries regarding to the production and distribution, which enable a complete tracking
of a batch, are filed in an organized manner, with easy access;
VIII warehouse is suitable and the distribution of products minimizes any risk to quality;
IX is implanted a system able to collect any batch after is commercialization or distribution; and
X claims on commercialized products are examined, registered and the causes of deviations of
quality are investigated and documented. It shall be taken measure regarding products with quality
deviation and adopted the arrangements in a way to refrain recidivation.
CHAPTER III
SANITATION AND HYGIENE
Article 14. Medications production requires a high level of sanitation and hygiene that shall be
complied with in all its steps.
1st Sanitation and hygiene activities shall include personnel, facilities, equipment and utilities,
production materials and recipients, cleaning and disinfection products and any other aspect that
may constitute a contamination source for the product.
2nd Potential sources of contamination shall be eliminated through a wide program of sanitation
and hygiene.
CHAPTER IV
QUALIFICATION AND VALIDATION
Article 15. According to the GMPs, the company shall identify which qualification and validation
works are necessary to evidence that all the critical aspects of the operation are under control.
Article 16. The key elements of a company qualification and validation program shall be clearly
described and documented in a master plan of validation.
Article 17. Qualification and validation shall set forth and supply documented evidences on:

I facilities, utilities, computer systems, equipment and processes that have been designed
according to the requirements of the GMP (project qualification or QP);
II facilities, utilities, computer systems and equipment that have been built and installed as per its
project specifications (qualification of installation or QI);
III - facilities, utilities, computer systems and equipment that operate as per their planned
specifications (operation qualification or QO); and

IV an specific procedure shall consistently produce a product that complies with quality
specifications and assignments (process validation or VP, in some cases also called performance
qualification or QD)
Article 18. Any aspect of the operation, including significant changes in the facilities, place,
computer systems, equipment or procedures that may, direct or indirectly, affect the quality of the
product, shall be qualified and/or validated.
Article 19. Qualification and validation shall not be considered sole exercises. After approval of the
qualification and/or validation report, there shall be a continuous monitoring program, which shall
be based on a periodic inspection.
Article 20. The commitment of the maintenance of the qualification/validation situation shall be
described in the documents which are relevant to the company, such as the manual of quality or the
master plan of validation.
Article 21. The responsibility for the validation accomplishment shall be clearly defined.
Article 22. Validation studies are a essential part of the GMPs and shall be effected according to
pre-defined and approved protocols.
Article 23. Qualification and validation reports containing results and conclusions shall be prepared
and filed.
Article 24. Processes and procedures shall be brought about based on the results of the validation
done.
Article 25. It shall also be validated the cleaning procedures, analytical methods and the computer
systems.
CHAPTER V
CLAIMS
Article 26. All claims and other information regarding products with possible quality deviations
shall be carefully investigated and logged according to written procedures.
Sole Paragraph. It shall be adopted preventive and corrective actions when quality deviations are
evidenced.

Article 27. It shall be appointed a responsible person for the receipt of claims and for the measures
to be adopted.
1st This person shall provide enough support personnel to assist him in the function.
2nd If the person appointed is not a technical responsible, he shall be aware of any claim,
investigation or collection.
Article 28. There shall be written procedures that describe the actions to be adopted in case of claim
related to possible quality deviations of a product, including the need of a possible collection.
Article 29. It shall be given special attention to claims arising from possible falsifications or cargo
robbery.
Sole Paragraph. There shall be written procedures that describe the measures to be adopted,
including notification to the competent sanitation authorities.
Article 30. Any claim regarding quality deviation shall be logged with the original details provided
by the claimant and it shall be completely investigated.
Sole Paragraph. The person appointed by the Quality Assurance shall be involved in the
investigation of the deviation in question.
Article 31. If it detected quality deviation in any product batch, or if there is a suspect of deviation
in a determined batch, it shall be taken into consideration the possibility of other batches presenting
the same problem and, therefore, they shall be inspected.
Sole Paragraph. If other batches contain reincorporated product of the batch with deviation, these
shall be specially inspected.
Article 32. All decisions and measures taken as a result of a determined claim shall be logged and
referenced in the corresponding batch logs.
Article 33. The registries of claims shall be regularly revised aiming at detecting any indications of
specific or recurrent problems, which require greater attention and may justify the collection of the
commercialized products.
Article 34. The competent sanitation authorities shall be informed by the manufacturer or the log
holder when it is detected any significant quality deviation in the production process, product
deterioration, cargo robbery or, when it is investigated, any other problem that has impact in the
product quality.
CHAPTER VI
PRODUCTS COLLECTION

Article 35. There shall be a system that immediately and effectively collects from the market the
products that present quality deviations, or which are under suspicion, as per specific sanitation
legislation in effect.
Article 36. It shall be appointed a responsible person for the measures to be adopted and for the
coordination of the collection of the product from the market.
1st This person shall provide for enough support personnel to assist him in all the aspects of
collection and with the necessary degree of urgency.
2nd Usually, this person cannot be part of the sales department and, in case he is not the technical
responsible, he shall be informed of any measure effected.
Article 37. It shall be established the procedures for the organization of any collection activity.
Sole Paragraph. The company may be able to start an immediate collection in all the distribution
chain.
Article 38. There shall be a written procedure that described products collected in a safe and
separated area, while its destination is decided.
Article 39. All competent sanitation authorities of the countries to which the product have been sent
shall be immediately informed on any intention of collection of the product which presents or is
under suspicious of quality deviation.
Article 40. Logs of distribution of batches shall be promptly available and shall contain enough
information on distributors and direct clients, including exported products, and samples of clinical
trials and medical samples, in order to enable an effective collection.
Article 41. Progress of the collection process shall be monitored and registered.
1st Logs shall include the provision of the product.
2nd It shall be issued a final report, including reconciliation between the distributed and the
collected amounts of products, as per sanitation legislation in effect.
Article 42. The effectiveness of the collection provisions shall be periodically tested and evaluated.
CHAPTER VII
PRODUCTION AND/OR ANALYSIS AGREEMENT
Article 43. Production and/or analysis agreements shall be clearly defined, agreed and controlled, in
order to avoid mistaken interpretations that may result in a product, process or analysis of
unsatisfactory quality.

Item I
General
Article 44. All conditions set forth in the production and/or analysis agreement, including any
proposals for changes in the technical conditions, or those of other nature, shall be complied with
the product log.
Article 45. The agreement shall permit the contracting party to audit the contractors facilities.
Article 46. In case of analysis agreement, the final approval for liberation of a product for
commercialization shall be carried out by an appointed person by the Quality Assurance of the
contracting company.
Article 47. Guidelines regarding outsourcing of the production steps and of the analysis of the
quality control contained in this resolution does not exclude the accomplishment of the
determinations set forth in the specific legislation in effect.
Item II
Contracting Party
Article 48. The contracting party shall be responsible for the evaluation of the contractor's
competence in correctly realization the contracted processes or tests, for the approval of the
agreement activities, and further to assure, in the agreement, that the GMP principles set forth in
this resolution are followed.
Article 49. The contracting party shall provide the contractor with all necessary information for the
realization of the operations in a correct manner, as per the product log and any other legal
requirements.
Sole Paragraph. The contracting party shall assure the contractor is informed of any problems
associated to the product, process or trials that might put in risk the facilities, equipment, personnel,
materials or other products.
Article 50. The contracting party shall assure that all the processed products and materials delivered
by the contractor fulfill all the specifications and that these are released by a person appointed by
the Quality Assurance.
Item II
Contracting Party
Article 51. The contractor shall have suitable facilities, equipment and know-how, besides
experience and qualified personnel, in order to satisfactory perform the service requested by the
contracting party.
1st The production contracting may only be effected by manufacturers that hold an Operation
License and a Sanitation License for the productive activity.
2nd The parties shall fulfill the rules set forth in an specific legislation.

Article 52. The contractor is forbidden to outsource any part of the work granted to him in the
agreement.
Article 53. The contractor shall refrain from any activity that may affect, in a negative form, the
quality of the product for the contracting party.
Item IV
Agreement
Article 54. There shall be a written agreement between the contracting party and the contractor
which clearly sets forth the responsibilities of each party.
Article 55. The agreement shall clearly set forth as the person appointed by the Quality Assurance,
when releasing each product batch for sale or issuing an analysis certificate, exercises its full
responsibility and assures that each batch has been manufactured and verified as per log
requirements.
Article 56. The technical aspects of the agreement shall be settled by competent people, with
suitable knowledge in pharmaceutical technology, quality control and GMP.
Article 57. All procedures of production and quality control shall be complied with the product log
involved and shall be agreed by both parties.
Article 58. The agreement shall clearly describe the responsibilities for the acquisition, control trials
and release of materials, by the production and the realization of quality control, including controls
under process, and the responsibility for sampling as well.
Article 59. Production, analysis and distribution logs, as well as reference samples, shall be kept by
the contracting party or be available.
Sole Paragraph. Any relevant logs for quality evaluation of a product object of claims or under
suspicion of deviations shall be accessible and specified on the contracting partys procedures on
deviations/collection.
Article 60. The agreement shall describe management of raw material, intermediate products, bulk
and finished products, in case they are unapproved/rejected.
Sole Paragraph. The agreement shall also describe the procedures to be followed in case the
contracted analysis shows the tested product shall be not approved.
CHAPTER VIII
SELF-INSPECTION AND QUALITY AUDITING
Article 61. Self-inspection shall evaluate the fulfillment of the GMP by the manufacturer in all its
aspects.

1st The self-inspection program shall be planned to detect any deviation in the implementation of
the GMP and shall recommend the necessary corrective measures.
2nd Self-inspections shall be carried out in a routine manner and, moreover, it may be carried out in
special times, for instance, in case of collections, repeated rejections of products or before an
inspection to be carried out by a sanitation authority.
3rd The staff responsible for self-inspection shall be able to evaluate the implementation of the
GMP in an objective manner.
4th All recommendations of corrective measures shall be implemented.
5th Self-inspection procedure shall be documented and there shall be an efficient follow-up
program.
Item I
Self Inspection Items
Article 62. There shall be created a written procedure for self-inspection.
Sole Paragraph. The procedure may include questionnaires on the GMP requirements including at
least the following aspects:
I staff;
II facilities, including dressing rooms;
III buildings and equipment maintenance;
IV warehousing of raw materials, packing materials, intermediate products and finished products;

V equipment;
VI production and controls in the process;
VII quality control;
VIII documents;
IX sanitation and hygiene;
X validation and revalidation programs;
XI calibration of instruments and measurement systems;
XII collection procedures;

XIII management of claims;


XIV - labels control;
XV previous self-inspections results and any corrective measures taken;
XVI computer systems relevant to the Good Manufacturing Practices;
XVII transport of medications and intermediate products; and
XVIII waste management.
Item II
Self-Inspection Team
Article 63. Quality Assurance shall appoint a team to effect the self-inspection, formed by qualified
professionals, specialists in their own areas of operation and familiar to the GMPs.
Sole Paragraph. Team members may be professionals of the company itself or outsourced
specialists.
Item III
Self-Inspection Frequency
Article 64. The frequency with which self-inspections are conduced shall be set forth in the
procedure.
Sole Paragraph. The frequency shall depend on the features of the company, and preferably made
annually.
Item IV
Self-Inspection Report
Article 65. It shall be elaborated a report after the end of an inspection, which shall include:
I self-inspection results;
II evaluations and conclusions; and
III recommended corrective measures.
Item V
Follow Up Measures
Article 66. There shall be an efficient follow up program for self-inspection activities by the Quality
Assurance.
Sole Paragraph. The company management shall evaluate the reports of self-inspection and the
recommended corrective measures as well, if necessary.

Item VI
Quality Assurance
Article 67. Self-inspection completion with quality auditing might be necessary.
1st Quality auditing consists in an examination and in the evaluation, in the whole or in part, of a
determined quality system, with the specific aim of improving it.
2nd Generally, it is effected by outsourced, independent specialists, or by a team appointed by the
management for such purpose.
3rd Auditing shall be extended to outsourcers and contractors.
Item VII
Auditing and Outsourcers Qualification
Article 68. The person appointed by the Quality Assurance shall be responsible, together with other
relevant departments, to approve trustful suppliers of raw materials and packing materials which
fulfill the established specifications.
Article 69. Before the suppliers are included in the list of qualified suppliers, they shall be evaluated
as per a pre-determined procedure or program.
1st The evaluation shall include the accomplishment of the legal requirements, as well as take into
account the history and nature of the materials supplied.
2nd In case auditing is necessary, it shall be evidenced the capacity of the supplier in being
compliant to the GMP standards.
CHAPTER IX
PERSONNEL
Article 70. The establishment and maintenance of Quality Assurance system and the production of
medications depend on the people that effect it.
1st There shall be qualified personnel in amount enough to perform all the activities for which the
manufacturer is responsible.
2nd All the individual responsibilities shall be established in documents formarly approved and
shall be clearly included by all the involved.
Item I
General
Article 71. The manufacturer shall have the suitable number of employees with the necessary
qualifications and practical experience.

Sole Paragraph. The responsibilities given to an employee shall not be so extensive that could
present risks to the product quality.
Article 72. The company shall have a flowchart.
1st All the employees in responsibility position shall have their specific assignments written and
authority enough to perform them.
2nd Assignments may be delegated to appointed deputies who shall have a satisfactory qualification
level.
3rd There shall not be faults or non-justifiable super positions in the staff responsibilities when it
comes to the application of the GMP.
Article 73. All the staff shall meet the principles of the GMP and receive initial and continuous
training, including hygiene instructions, as it is needed.
Sole Paragraph. All the staff shall be motivated in supporting the company in the maintenance of
the quality standards.
Article 74. It shall be taken measures to avoid that non-authorized people get into the areas of
production, warehouse and quality control.
Sole Paragraph. The part of the staff that does not work in such areas shall not use them as passage
to other areas.
Item II
Key Personnel
Article 75. Key personnel includes the responsibles for the production, quality assurance, quality
control and the technical responsible.
1st Key positions shall be taken by people that work full time.
2nd The responsible for the production and quality control shall be independent from each other.
3rd In some companies, it may be necessary to delegate some functions; however, responsibility
cannot be delegated.
Article 76. Key personnel responsible for production, quality assurance and quality control of
medications shall have practical experience and the qualification required by legislation.
Sole Paragraph. Level of instruction shall include studies of a combination of the following fields of
knowledge:
I Analytical and Organic Chemistry or Biochemistry;

II Microbiology;
III Technology and pharmaceutical sciences;
IV Pharmacology and Toxicology;
V Physiology; and
VI other related sciences.
Article 77. Responsibles for Production, Control and Quality Assurance shall jointly exercise some
activities related to quality, such as:
I authorization of procedures and documents, including their update;
II monitoring and control of the production environment;
III establishment and monitoring of the hygiene conditions;
IV - validation of process and calibration of the analytical instruments;
V training, including the application of the principles of quality guarantee;
VI approval and monitoring of materials suppliers;
VII approval and monitoring of the contracted manufacturers;
VIII specifications and monitoring of the warehousing conditions of materials and products;
IX controls in process;
X file of documents/logs;
XI GMP compliance monitoring; and
XII inspection, investigation and sampling, in order to monitor factors that may affect product
quality.
Article 78. The responsible for the production has the following responsibilities:
I assure the products are produced and stored as per suitable procedures, aiming at reaching the
required quality;

II approve the instructions related to production operations, including the controls in process, and
assure the strict implementation of them;
III assure the production registries are evaluated and signed by an appointed person;

IV - inspect the maintenance of the installations and equipment;


V - assure validations of processes, calibrations and equipment control are executed and logged
and that reports are available; and

VI assure that there is an initial and continuous training suitable to the needs of the personnel of
the production area.
Article 79. The responsible for the Quality Control has the following responsibilities:
I - approve and reject raw materials, packing materials and intermediate products, bulk or finished
regarding its specification;
II - evaluate the analytical logs of batches;
III assure that all necessary trials are done;
IV - take part in the elaboration of sampling instructions, specifications, trial methods and
procedures of quality control;
V approve and monitor the analysis done, under contract;
VI inspect the maintenance of the installations and equipment of quality control;
VII assure that it is made the necessary validations, including the validation of the analytical
methods and calibration of the control equipment; and
VIII assure that it is carried out the initial and continuous training of the personnel of the Quality
Control area, as per the needs of the sector.
Article 80. The responsible for the Quality Assurance has the following
responsibilities: I review the documents of the batches produced;
II approve or reject finished products for commercialization;
III in a final character, approve all the documents related to the Good Manufacturing Practices;
IV - assure the correct fulfillment of the validation activities;
V - coordinate the activities related to the investigation of deviations and adoption of preventive
and corrective measures;
VI suitably investigate the claims received;
VII coordinate the system of changes control;

VIII coordinate and take part of the self-inspections and auditings program;
IX assure the execution of a continuous program of training; and
X coordinate collection measures.
Article 81. The release of a batch or a finished product may be delegated to a person with suitable
qualification and experience, which shall release the product as per the approved procedures
through the revision of the batch documents.
Article 82. The person appointed for approval or liberation of a batch shall always assure the
following requirements have been fulfilled:
I the batch has been produced as per the registry of the product;
II principles and guidelines of the Good Manufacturing Practices have been followed;
III - manufacturing and control processes have been validated;
IV all necessary tests and inspections have been carried out, considering the production conditions
and registries;

V any planned changes, production deviations or in the quality control have been notified and
investigated before release. - Such changes may need notification and approval of the ruling
authority.
VI any additional measures of sampling, inspection, tests and verifications shall be carried out or
initiated to comply with the planned changes or with the deviations found;

VII all necessary documents of production and quality control have been concluded and approved
by the respective responsibles;
VIII auditings, self-inspections and suitable punctual verifications have been carried out by
experienced and trained teams;
IX - quality control attested the full accomplishment of the specifications; and
X all the relevant factors have been considered, including any other not specifically associated to
the production batch under review.
Article 83. If a determined batch does not comply with the specifications or presents any
divergence, this shall be investigated.
1st If needed, investigation shall be extended to the other batches of the same product or of the
other products that have bound to the detected deviation.

2nd There shall be an investigation log, which shall contain the conclusion and the necessary
follow-up measures.
Article 84. The Technical Responsible shall assure the fulfillment of the technical and ruling
requirements regarding the quality of the finished products.
Article 85. The Technical Responsible shall also assure the realization of other activities, including
the following:
I implementation and establishment of the quality system;
II development of the manual of quality of the company;
III self-inspections;
IV - external auditing (suppliers auditing); and
V validation programs.
CHAPTER X
TRAINING
Article 86. The manufacturer shall train the personnel involved with activities of quality assurance,
production, quality control, as well as all the personnel whose activities may interfere in the quality
of the product, upon a written and defined program.
Article 87. Recently contracted personnel shall receive specific training to their work positions,
besides basic training on GMP theory and practice.
1st It shall also be provided a continuous training and its practical effectiveness shall be
periodically evaluated.
2nd It shall be available training programs approved and it shall be kept the training logs.
Article 88. Personnel that work in clean areas, in areas with contamination risk and also areas of
manipulation of highly active, toxic, infectious and sensibilizing materials, shall receive specific
training.
Article 89. The concept of quality assurance and all the measures that assist its understanding and
implementing shall be totally discussed during the training sessions.
Article 90. Visitors and non-trained personnel shall preferably not be into the production and quality
control areas.
Sole Paragraph. If it is unavoidable, visitors and non-trained personnel shall receive previous
relevant information, mainly on personal hygiene, as well as on the use of suitable protection
clothing.

Article 91. Consultant and contractors teams shall be qualified for the training services they
provide. It shall be included evidences of qualification in the training logs.
CHAPTER XI
PERSONAL HYGIENE
Article 92. All personnel shall be submitted to periodical health exams, including those of
admittance or dismissal.
Sole Paragraph. Employees that conduct visual inspections shall also be submitted to periodical
exams of visual acuity.
Article 93. All the staff shall be trained in the practices of personal hygiene.
1st All the people involved in the production process shall comply with the rules of hygiene and,
mainly, they shall be instructed to suitably wash their hands before they get into the production
areas.
2nd It shall be fixed and observed the instructive signals for hand washing.
Article 94. People with suspicion or confirmation of an infirmity or exposed injury that may
adversely affect the quality of the products shall not handle raw materials, packing materials,
intermediate products and bulk or finished products until their health conditions does not represent a
risk to the product.
Article 95. All employees shall be instructed and incentivized to report to their immediate
supervisor any conditions regarding production, equipment or personnel, which they consider that
could adversely interfere in the products.
Article 96. It shall be avoided the direct contact between the operator's hand and the raw materials,
primary packing materials, intermediate and bulk products.
Article 97. Employees shall use clean clothing and suitable to each production area in order to
assure the protection of the production against contamination.
Sole Paragraph. The uniforms, when they are reusable, shall be set apart in closed environment until
they are cleaned and, as the case may be, disinfected or sterilized.
Article 98. Uniforms shall be supplied by the manufacturer as per written procedures.
Sole Paragraph. Washing the uniforms is a company responsibility.
Article 99. In order to assure the employees protection, the manufacturer shall enable Collective
Protection Equipment (CPE) and Personal Protection Equipment (PPE) as per the activities
developed.

Article 100. Smoking, eating, drinking, chewing or keeping plants, food, beverages, smoke and
personal medications is forbidden in the laboratory of quality control, in the production and storage
areas, or in any other areas in which such actions may adversely influence in the product quality.
Article 101. Procedures of personal hygiene, including the use of suitable clothing, shall be applied
to all of those who get into the production areas.
CHAPTER XII
FACILITIES
Article 102. Facilities shall be located, planned, built, adapted and maintained suitable to the
operations to be carried out.
Item I
General
Article 103. The project shall minimize the mistakes and enable cleaning and maintenance, in a way
to avoid cross-contamination, dust and dirt accumulation or any other adverse effect that could
affect the products quality.
Article 104. It shall be taken measures to avoid cross contamination and to ease cleanness when
there is dispersion of dust, as during the operations of sampling, weighting, mixture, processing and
packing of dust.
Article 105. Facilities shall be situated in a place that, when considered together with the measures
to protect the manufacturing process, it presents a minimum risk to cause any contamination of
materials and products.
Article 106. Facilities used in the production of medications shall be projected and built in a way to
enable suitable cleaning.
Article 107. The facilities shall be maintained in good state of conservation, hygiene and cleanness.
Sole Paragraph. It shall be assured that the maintenance and repair operations do not represent any
risk to the products quality.
Article 108. Facilities shall be clean and, when applicable, disinfected, as per detailed written
procedures.
Sole Paragraph. Cleaning logs shall be kept.
Article 109. Provisioning of electric energy, lightning, temperature, humidity and ventilation of the
facilities shall be suitable, in a way to not affect, direct or indirectly, the quality of the medications
during the production processes or the suitable operation of the equipment.
Article 110. Facilities shall be planned and equipped to offer the maximum protection against the
ingress of insects, birds or other animals.

Sole Paragraph. There shall be a procedure for the control of plagues and rodents.
Article 111. Installations shall be planned to guarantee the logical flow of materials and personnel.
Item II
Auxiliary Areas
Article 112. Restrooms and dinning rooms shall be separated from the production and control areas.
Article 113. Clothing and toilet facilities shall be easily accessible and suitable for the number of
users.
Sole Paragraph. Toilets shall not have direct communication with the production and warehousing
areas.
Article 114. Maintenance areas shall be situated in places apart from the production areas.
Sole Paragraph. If tools and spare parts are kept in the production areas, they shall be set apart in
rooms or lockers reserved for this purpose.
Article 115. Nursery shall be isolated from the other areas, possess a separated entrance and an
exclusive ventilation system.
Item III
Warehouses
Article 116. Warehouses shall have capacity enough to enable the ordinate storage of materials and
products: Raw materials, packing materials, intermediate products, bulk and finished products,
those in quarantine, approved, unapproved, returned or collected, with the suitable separation.
Article 117. Warehouses shall be projected or adapted to assure ideal conditions of storage; they
shall be clean, dry, organized, and kept within the limits of temperature compatible with the storage
materials.
Sole Paragraph. If special storage conditions are needed, such as temperature and humidity, these
shall be provided, controlled, monitored and registered.
Article 118. Receipt and expedition areas shall be separated and shall protect the materials and
products from weather variations.
1st When separation is not possible, it shall be adopted suitable procedures to avoid intermingling.
2nd The receipt area shall be projected and equipped to permit the recipients are clean, if needed,
before storage.

Article 119. Products in quarantine shall be in a restrict and separated area in the warehouse.
1st The area shall be clearly marked and the access to this shall only be made by authorized people.
2nd Any other system that replaces the physical quarantine shall offer equivalent levels of safety.
Article 120. Storage of materials or returned, unapproved or collected products shall be effected in
an identified and physically isolated area.
Article 121. Highly active and radioactive materials, narcotics, other danger medications or
substances that present special risk of abuse, fire or explosion shall be warehoused in safe and
protected, identified and, when appropriate, dully segregated areas, according to specific legislation
in effect.
Article 122. It shall be given special attention to safe sampling and warehousing of materials of
printed packing, for being considered critical to the quality of the medications when it comes to
labeling.
Article 123. There shall be a specific area for sampling of raw materials.
Sole Paragraph. Sampling shall be conducted in order to avoid contamination or cross
contamination.
Item IV
Weighting Area
Article 124. The areas destined to weighting of raw materials may be located in the warehouse or in
the production area, and shall be specific and projected for this purpose, with an independent and
suitable exhaustion system which could avoid cross contamination.
Item V
Production Areas
It shall be used segregated and dedicated areas for the production of determined medications, such
as certain biological preparations (i.e., micro-organisms) and highly sensibilizing materials (i.e.,
penicillins, cephalosporins, carbapenems and other beta-lactam derivations), in a way to decrease
the risk of serious damages to health due to cross contamination.
1st In some cases, such as highly sensitive materials, segregation shall also occurr among them.
2nd The production of some highly active products such as antibiotics, some hormones, citotoxic
substances, shall be carried out in segregated areas.
3rd In peculiar cases, such as claims (fire, flood, etc.) or emergency situations (war, etc.), the
principle of work in the same facilities may be accepted, since it is taken some specific measures
and it is made the necessary validations (including cleaning validation).

Article 126. When it is produced highly active or highly sensibilizing medications, it shall be used
systems suitable for air treatment and exhaustion.
Article 127. It shall be provided physical facilities, as per the continuous operational floor, in order
the production corresponds to the sequence of operations of production and to the level required of
cleaning.
Article 128. The production areas, including warehouses of materials in process, shall enable the
logical and ordinate positioning of equipment and materials, in order to decrease the risk of
intermingling among different medications or their components, avoid the occurrence of cross
contamination and decrease the risk of omission or mistaken application of any step of production
or control.
Article 129. In areas where raw materials, primary packing materials, intermediate or bulk products
are exposed to the environment, the inner surfaces (walls, ground and ceiling) shall be revested of
an even, impermeable, washable and resistant material, free from seams and cracks, of easy
cleaning, which enables disinfection and does not release particles.
Article 130. Pipes, luminaries, ventilation points and other installations shall be projected and
installed to ease cleaning.
Sole Paragraph. Always when possible, the access for maintenance shall be located externally to the
production areas.
Article 131. Graters shall be of suitable size, installed in order to avoid liquid or gases reflows and
be kept closed when they are not in use.
Sole Paragraph. It shall be avoided the installation of open channels; if necessary, these shall be
shallow to ease cleaning and disinfection.
Article 132. Production areas shall have an air treatment system suitable to the handled products, to
the operations carried out and to the external environment.
1st The treatment system shall include air filtering suitable to avoid contamination and cross
contamination, temperature control and, when necessary, humidity and pressure differentials
controls.
2nd Production areas shall be regularly monitored in order to assure the fulfillment of the
specifications.
Article 133. Installations for medications packing shall be specifically planned and built in order to
avoid intermingling or cross contamination.
Article 134. Production areas shall be well illuminated, mainly where there are visual controls.
Item IV

Areas of Quality Control


Article 135. Laboratories of quality control shall be separated from the production areas.
Sole Paragraph. Areas where it is employed biological, microbiological or radioisotope trials shall
be separated one from the other.
Article 136. The laboratories of quality control shall be suitable to the operations to which they
were made.
1st There shall be room enough to avoid intermingling and cross contamination.
2nd There shall be suitable room storage of samples, reference standards (if necessary, with
refrigeration), solvents, reagents and logs.
The areas where it was done the biological, microbiological or radioisotope trials shall be
independent and separated and count on independent installations, mainly the air system.
Article 138. It might be necessary the use of separated rooms to protect some instruments from
electric interference, vibrations, excessive contact with humidity and other external factors.
CHAPTER XIII
EQUIPMENT
Article 139. Equipment shall be designed, built, adapted, installed, located and maintained in order
they are suitable for the operations to be carried out.
Sole Paragraph. The project and location of equipment shall decrease the risks of errors, enable
suitable cleaning and maintenance, in order to avoid cross contamination, dust and dirt
accumulation and avoid a negative effect in the quality of the products.
Article 140. Equipment shall be installed in order to decrease any risk of mistake or contamination.
Article 141. A fixed piping shall be clearly identified, as per legislation in effect, to indicate the
content and, when applicable, flow direction.
Article 142. All pipes and appliances shall be suitably identified and shall give preference to the use
of non-interchangeable connections or adapters for dangerous gases and liquids.
Article 143. Balances and measurement instruments of the areas of production and quality control
shall have the working area and the precision required, and shall be periodically calibrated.
Article 144. Production equipment shall be cleaned, as per cleaning procedures approved and
validated, when its applicable.
Article 145. Analytical equipment and instruments shall be suitable to the methods carried out.

Article 146. Equipment of washing, cleaning and drying shall be chosen and used in a way not to
represent a contamination source.
Article 147. Equipment used in the production shall not present any risks for the products.
Sole Paragraph. The equipment parts in direct contact with the product shall not be reactive,
addictive or absorptive in order to interfere in the product quality.
Article 148. All unused or defective equipment shall be taken from the production areas and from
the quality control.
Sole Paragraph. When it is not possible unused or defective equipment shall be dully identified to
avoid its use.
Article 149. Closed equipment shall be used always when appropriate.
Sole Paragraph. When open equipment is used, or when they are open during any operation, it shall
be taken precautions to decrease contamination.
Article 150. Not dedicated equipment shall be clean as per cleaning procedures validated to avoid
cross contamination.
Article 151. In case of dedicated equipment, it shall be used validated cleaning procedures,
considering residuals of cleaning agents, microbiological contamination and degradation products,
when applicable.
Article 152. It shall be kept updated drawings of the equipment and of the critical support systems.
CHAPTER XIV
MATERIALS

Article 153. In the concept of materials, it is included raw materials, packing materials, gases,
solving agents, auxiliary materials to the process, reagents and labeling materials.
Item I
General
Article 154. No material used in operations such as cleaning, equipment lubrication and control of
plagues shall get in direct contact with the product.
Sole Paragraph. Materials shall be of suitable quality in order to decrease health risks.
Article 155. All entrance materials and finished products shall be immediately put in quarantine
after the receipt or production, until it is released for use or commercialization.

Article 156. All materials and products shall be warehoused in suitable conditions determined by
the manufacturer, in an ordinate manner to enable segregation of batches and storage rotation,
accoding to the first expires, first out" rule.
Article 157. Water used in the production of pharmaceutical products shall be suitable for the
intended use.
Item II
Raw materials
Article 158. Raw materials acquisition shall be carried out by a qualified and trained team.
Article 159. Raw materials shall be acquired only from suppliers approved by the company,
preferably, directly from the producer.
1st Specifications established by the manufacturer regarding raw materials shall be discussed with
suppliers.
2nd All aspects of production and raw material control, acquisition process, handling, labeling and
requirements regarding packing, as well as claims and unapproval procedures, shall be discussed
between the manufacturer and the suppliers.
Article 160. For each delivery, recipients shall be verified at least regarding integrity of the package
and lock, as well as regarding the correspondence among the order, the delivery note and the
suppliers labels.
Article 161. All received materials shall be verified in order to assure delivery is in compliance with
the order.
1st Recipients shall be clean and labeled with the necessary information.
2nd When it is used internal identification labels, these shall be enclosed to the recipients so that
original information is kept.
Article 162. Damages in recipients or any other problems that may affect the quality of the raw
material shall be logged, reported to the quality control department and investigated.
Article 163. If the delivery of the material contains different batches, each batch shall be
individually sampled, analyzed and released.
Article 164. Raw materials put in storage area shall be suitably identified.
1st Labels shall contain, at least, the following information:
I raw material name and the respective internal code of reference, when applicable;
II Manufacturers name and the respective batch number;

III when applicable, batch number attributed to the supplier and the batch number given by the
company at the receipt moment;
IV - raw material status in storage (in quarantine, in analysis, approved, unapproved, returned); and
V production date, retest date or validation term and reanalysis date, when applicable.
2nd It is permitted identification per validated electronic system. In this case, its not necessary to
put in the label all information described above.
Article 165. There shall be procedures or suitable measures to assure the identity of the content of
each container of raw material.
Sole Paragraph. Containers from which it had been taken samples shall be identified.
Article 166. Only raw materials released by the department of quality control and which are within
the term for its use shall be released.
Article 167. Raw materials shall be handled only by appointed employees, as per written
procedures.
Sole Paragraph. Raw materials shall be carefully weighted or measured in clean and correctly
identified containers.
Article 168. Weighted or measured raw materials, as well as their respective weights and volumes,
shall be checked by other employee or an automated system of checking, and logs shall be kept.
Article 169. Weighted or measured raw materials for each production batch shall be kept together
and visibly identified as such.
Item III
Packing Material
Article 170. Acquisition, handling, and quality control of the primary, secondary packing, and of
printed materials, shall be carried out in the same manner for the raw materials.
Article 171. Printed packing materials shall be warehoused in safe conditions in a way to exclude
the possibility of non-authorized access.
1st Labels in bobbins shall be used always when possible.
2nd Fractioned labels and other lose printed materials shall be warehoused and transported in
closed and separated containers in a way to avoid intermingling.
3rd Packing materials shall be sent to production only by appointed personnel, following an
approved and documented procedure.

Article 172. Each batch of packing material, including printed material, shall receive a specific
reference number or identification mark.
Article 173. Printed materials, unupdated and obsolete primary and secondary packing shall be
destructed and this procedure shall be registered.
Article 174. All products and packing materials to be used shall be verified upon delivery to the
packing department regarding to quantity, identity and compliance with packing instructions.
Item IV
Intermediate and Bulk Products
Article 175. Intermediate products and bulk products shall be kept under specific conditions,
determined for each product.
Article 176. Intermediate products and bulk products acquired shall be handled upon receipt as raw
materials.
Item V
Finished Products
Article 177. Finished products shall be kept in quarantine up to its final release.
Sole Paragraph. After its release, finished products shall be warehoused as available warehouse,
according to the conditions set forth by the manufacturer.
Item VI
Unapproved, Recovery and Reprocessed Materials
Article 178. Unapproved materials and products shall be identified as such and warehoused
separately, in restrict areas.
Sole Paragraph. Such materials and products may be returned to the suppliers or, when applicable,
reprocessed or destructed within a justifiable term and the action adopted shall be approved by an
appointed person.
Article 179. Reprocess or recovery of unapproved products shall be exceptional.
1st Reprocess or recovery is permitted only if the quality of the final product is not affected, their
specifications are complied with and also if it's made in accordance with a defined and authorized
procedure after evaluation of the risks involved.
2nd It shall be kept a registry of reprocess or recovery.
3rd A reprocessed or recovered batch shall receive a new batch number.

Article 180. The introduction of previous batches, or part of these, in compliance to the quality
required, in a batch of same product in a given step of production, shall be previously authorized.
1st This recovery shall be made as per a fixed procedure, after evaluation of the risks involved,
including any possible effect on the validity term.
2nd Recovery shall be registered.
Article 181. The need of additional tests of any finished products that had been reprocessed, or that
had suffered incorporation, shall be considered by the Quality Control.
Item VII
Collected Products
Article 182. Products collected shall be identified and warehoused separately in a safe area until
there is a decision on its destination.
Sole Paragraph. The decision shall be taken the soonest possible and in compliance with specific
legislation on the collection of medications.
Item VIII
Returned Products
Article 183. Returned products shall be destroyed, unless it is possible to assure its quality is
satisfactory; in such cases, it may be considered for resale, new labeling, or alternative measures
only after critical evaluation by the quality area, as per written procedure.
1st It shall be considered in the evaluation the nature of the product, any special conditions of
warehousing, its condition and history, as well as the time elapsed from its expedition.
2nd In case of doubt on the quality, the returned products shall not be considered suitable for new
expedition or reuse.
3rd Any measure taken shall be registered.
Item IX
Reagents and Culture Means
Article 184. There shall be logs for receipt and preparation of reagents and culture means.
Article 185. Prepared reagents shall be elaborated as per written procedures, suitably labeled and
kept in preparation logs.
1st The label shall indicate the concentration, date of preparation, standardization factor, validation
term, date of the next standardization and warehousing conditions.
2nd Label shall be signed and dated by the person that prepared the reagent.

Article 186. It shall be made positive controls, as well as negative ones, so that it is verified the
suitability of the culture means.
Sole Paragraph. The inoculums size used in the positive controls shall be suitable to the
sensitiveness required.
Item X
Reference Standards
Article 187. It shall be used official reference standards, whenever they exist.
Sole Paragraph. In their absence, it shall be used dully characterized reference standards.
Article 188. A non-acquired reference standard of an acknowledged pharmacopeia shall be of the
most elevated degree of purity possible and carefully characterized in order to guarantee its identity,
tenor, quality, purity and powerfulness.
1st Qualitative and quantitative analytical procedures employed to characterize a reference standard
shall be more extensive from those used to control identity, tenor, quality, purity and powerfulness
of the drug or medication.
2nd Analytical procedures used to characterize a reference standard shall not be based only on
comparison tests of a reference standard previously characterized.
3rd Characterization documents shall be available and be kept under responsibility of an appointed
person.
Article 189. Official reference standards shall be used only for the purpose described in the
respective monograph.
Article 190. Reference standards shall be warehoused as per the manufacturers recommendations.
Sole Paragraph. The manufacturer's recommendations shall be followed regarding the correct usage,
including pre-treatment (drying, correction of content, etc) of these substances.
Article 191. All secondary and work standards shall be standardized regarding a reference standard.
Article 192. If it is necessary, it shall be carried out suitable inspections in regular intervals with the
purpose of assuring standardization of secondary standards.
Article 193. All reference standards shall be warehoused and used to not negatively affect its
quality.
Item XI
Residual Materials

Article 194. It shall be taken provisions regarding the appropriate and safe care of the residual
materials to be eliminated.
Sole Paragraph. Toxic substances and flammable materials shall be set apart in places of restrict
access, as per required by the legislation in effect.
Article 195. The residual material shall be collected in suitable recipients, kept in specific place and
safely eliminated in regular and frequent intervals, as per sanitation rules.
Sole Paragraph. Residual material shall not be accumulated.
Item XII
Several Materials
Article 196. It shall not be permitted that raticide products, insecticides, fumigants agents and
sanitizing materials contaminate equipment, raw materials, packing materials, materials in process
or finished products.
CHAPTER XV
DOCUMENTS
Article 197. Documentation constitutes an essential part of the Quality Assurance system and shall
be related to all aspects of the GMP.
1st Documentation aims at describing the specifications of all the materials and production and
control methods in order to assure that all personnel involved in the production learns to decide
what to do and when to do it.
2nd Documentation aims at assuring that the appointed person has all the necessary information to
decide on the release of a determined batch of medication for sale, enable tracking that permits
investigation of the history of any batch under suspicion of quality deviation and assuring the
availability of the necessary data for validation, revision and statistical analysis.
3rd All document shall be easily available, gathered in a sole folder or apart.
Item I
General
Article 198. Documents shall be written, reviewed, approved and distributed only to appointed
people.
Sole Paragraph. It shall fulfill all the steps of production authorized by the registry.
Article 199. Documents shall be approved, signed and dated by the appointed person.
Sole Paragraph. No document shall be modified without previous authorization and approval.
Article 200. Content of documents cannot be ambiguous.

1st The title, nature and its aim shall be presented in a clear, precise and correct form.
2nd It shall be provided in an ordinate form and it shall be of easy verification.
3rd Reproduced documents shall be legible and assure its fidelity to the original.
Article 201. Documents shall be regularly reviewed and updated.
1st When a determined document is reviewed, there shall be a system that impairs the inadvertent
use of the obsolete version.
2nd Obsolete documents shall be kept for an specific period of time set forth in the procedure.
Article 202. When documents require data input, these shall be clear, legible and indelible.
Sole Paragraph. It shall be left space enough for data input.
Article 203. All alteration effected in any document shall be signed, dated and enable reading of the
original information.
Sole Paragraph. As the case may be, the reason of the alteration shall be logged.
Article 204. It shall be kept logs of all the actions effected in such a way that all significant
activities regarding medications production may be tracked.
Sole Paragraph. All logs may be filed for at least one year after the expiration date of the finished
product.
Article 205. Data may be registered by a system of electronic processing, through photographic
means or other trustworthy ones.
1st Master formula/standard formula and the Standard Operational Procedures regarding the system
in use shall be available and the accuracy of logged data shall be verified.
2nd Data logging is made through electronic processing, only appointed people may modify data
contained in the computers.
3rd There shall be a log of the alterations carried out.
4th Access to computers shall be restricted by passwords or other means.
5th Input of critical considered data, when manually inserted in a system, shall be checked by an
appointed person.

6th Electronic logs of batch data shall be protected by magnetic tape, microfilm, printing in paper
or other means.
7th During the retention period, data shall be promptly available.
Item II
Labels
Article 206. The identification fixed in the recipients, in equipment, in facilities and in the products
shall be clear, without ambiguity, and in a format approved by the company, containing the
necessary data.
Sole Paragraph. In addition to the text, it may be used different colors that indicate its condition (in
quarantine, approved, unapproved, clean, among others).
Article 207. All finished products shall be identified, as per legislation in effect.
Article 208. Labels of the reference standards and documents that follow it shall indicate the
concentration, production date, date in which lock has been open, warehousing conditions and,
when applicable, expiration term and the control number.
Item III
Specifications and Quality Control Trials
Article 209. Quality control methods shall be validated before they are adopted in the routine,
taking into consideration facilities and available equipment.
Sole Paragraph. Analytical methods from manuals do not require validation, however, before its
implementing, there shall be documented evidences of its suitability to the operational conditions of
the laboratory.
Article 210. All raw materials specifications, packing materials and finished materials shall be dully
authorized, signed and dated, as well as kept by the Quality Control or the Quality Assurance.
Article 211. It shall be carried out trials in the intermediate products and in the bulk products, when
applicable.
Sole Paragraph. There shall also be specifications regarding water, solvents and other reagents
(acids and basis) used in the production.
Article 212. It shall be done periodical revisions of the specifications in order they are updated as
per the new editions of the national pharcopeia or other official manuals.
Article 213. Pharmacopeias, reference standards, spectrometry references and other necessary
reference materials shall be at the disposal of the laboratory of quality control.
Item IV

Specifications in Raw materials and Packing Materials


Article 214. Specifications of raw materials, primary packing materials and printed materials shall
have a description, including, at least:
I internal reference code and name as per the DCB, if any;
II - reference of the pharmacopoeia essay, if any; and
III quantitative and qualitative requirements with the respective limits of acceptance.
1st Depending on the practice adopted by the company, it may be added other data to the
specifications, such as:
I identification of the supplier and of the original producer of the materials;
II sample of printed material;
III guidelines on sampling, quality tests and references used in the control procedures;

IV - warehousing conditions and precautions; and


V maximum term of warehousing before another new analysis is taken place.
2nd Packing materials shall fulfill the specifications emphasizing its compatibility with other
medications.
3rd The material shall be examined when it comes to the presence of defects and correct
identification marks.
Article 215. The documents with the description of the procedures of control trials shall indicate the
frequency of the execution of trials of each raw material, as per determined by its stability.
Item V
Specifications on Intermediate and Bulk Products
Article 216. Specifications on intermediate and bulk products shall be available when this material
is acquired or dispatched, or if data on the intermediate products is used in the evaluation of the
final product.
Sole Paragraph. These specifications shall be compatible to the specifications regarding to raw
material or to finished products.
Item VI
Specifications on Finished Products

Article 217. Specifications for finished products shall include:


I generic name of the product and brand or commercial name, as the case may be;
II names of the active ingredient with its respective DCB;
III formula or its reference;
IV - pharmaceutical form and packing details;
V references used in sampling and in control trials;
III quantitative and qualitative requirements with the respective limits of acceptance;
VII conditions or precautions to be taken in warehousing, as the case may be; and
VIII validity term.
Item VII
Master/Standard Formula
Article 218. There shall be an authorized master/standard formula for each product and batch size to
be produced.
Article 219. Master/standard formula shall include:
I product name with the reference code regarding its specification;
II description of the pharmaceutical form, product concentration and batch size;
III list of all raw materials to be used (with the respective DCB); with the amount used in each
one, using the generic name and reference which are exclusive for each material. It shall be
mentioned to any substance that may disappear during the process;
IV statement on the final efficiency expected, with acceptable limits, and intermediate efficiency,
as the case may be;
V Indication of the processing place and equipment to be used;
VI methods (or reference) to be used in the preparation of the main equipment, such as cleaning
(mainly after product change), assembly, calibration and sterilization;
VII detailed instructions of the steps to be followed in production (inspection of materials, pretreatments, sequence of the addition of materials, times of mixture, temperatures, etc.);

VIII instructions regarding any controls in preocess with their acceptance limits;
IX requirements regarding conditioning of products, including on container, labeling and any
special warehousing conditions; and
X any special precautions to be observed.
Item VIII
Packing Instructions
Article 220. There shall be authorized instructions regarding the packing process, regarding each
product and to the size and type of packing.
1st Instructions shall include the following data:
I product name:
II description of its pharmaceutical form, its concentration and administration, as the case may be;

III packing size, expressed in number, weight or volume of the product contained in the final
container;
IV complete list of all the packing material necessary for the standard batch size, including
amounts, sizes and types, with reference code and number regarding the specifications of each
material;
V sample or reproduction of materials used in the packing process, includign the place where the
batch number and its due date shall be printed or recorded;
VI special precaution, such as verification of the equipment and of the area in which packing
shall take place, in order to guarantee the absence of printed materials of previous products in the
packing lines;
VII description of the operations of packing and equipment to be used; and
VIII details on the controls in process, together with the instructions on sampling and the
acceptance criteria.
Item IX Logs of
Batches Production
Article 221. It shall be made logs on the production of each batch.
Sole Paragraph. Logs shall be based on the master/standard formula approved and in use, avoiding
transcription errors.

Article 222. Before starting a production process, it shall be verified if the equipment and the place
of work are free from products previously produced, a well as if it is available the documents and
materials necessary for the planned process.
1st It shall be verified if equipment is clean and suitable for use.
2nd Such inspections shall be logged.
Article 223. During the production process, all the developed steps shall be registered, including the
initial and the final time of execution of each operation.
1st Logs of the execution of such steps shall be dully dated by the executors, clearly identified by
signature or electronic password and ratified by the area supervisor.
2nd Logs of production batches shall contain at least the following information:
I product name;
II batch number that is being produced;
III dates and times of beginning and finishing of the main intermediate steps of production;
IV - name of the person responsible for each production step;
V identification of the operators of the different production steps and, when appropriate, of the
person that verifies each one of these operations;
VI batch number and/or the number of the analytical control and the amount of each row-material
used, including batch number and the amount of any material recovered or reprocessed that has
been added;
VII any relevant operation or event observed in the production and the main equipment used;
VIII controls in process carried out, the identification of the person that had executed and the
results obtained;
IX the amounts obtained of the product in the different steps of production (efficiency), together
with comments or explanations on any significant deviations of the expected efficiency; and
X comments on special problems, including details such as a signed authorization for each
alteration of the production formula or production instructions.
Item X
Logs of Batches Packages
Article 224. It shall be kept packing logs of each batch or part of a batch, as per packing
instructions.

Sole Paragraph. Logs shall be prepared in a way to avoid transcription mistakes.


Article 225. Before the beginning of any packing operation, it shall be verified if equipment and the
work stations are free from previous products, documents and materials not required for the planned
packing operations, and that the equipment is clean and suitable for use.
Sole Paragraph. Such inspections shall be logged.
Article 226. During the production process, all the developed steps shall be registered, including the
initial and the final time of execution of each operation.
1st Logs of the execution of each step shall be dully dated by the executors, clearly identified by
signature or electronic password and ratified by the area supervisor.
2nd Logs of production batches shall contain at least the following information:

I - product name, batch number and the amount of the bulk product to be packed, as well as the
batch number and the amount planned of the finished product that shall be obtained, the amount
currently obtained and reconciliation;
II - dates and times of packing operations;
III name of the responsible person for the packing operation;
IV - identification of the operators in the main steps;
V - inspections made regarding to identification and compliance with instructions for packing,
including the results of the controls in process;
VI details of the packing operations, including references to equipment, to the lines of packing
used and, when necessary, the instructions and registries regarding the warehousing of non-packed
products;

VII samples of printed packing materials used, including samples containing the approval for
printing and regular inspection (when appropriate), containing batch number, production date,
expiration date and any additional printing;
VIII comments on any special problems, including details on any deviation from the packing
instructions, with written authorization of the appointed person;
IX the amounts of all the printed packing materials with reference or identification number, and
bulk products delivered to be packed; and
X amounts of all the materials used, destroyed or returned to storage and the amount obtained of
the product, in order it can be made a correct reconciliation.

Item XI
Standard Operational Procedures (SOP) and Logs
Article 227. Standard Operational Procedures and logs associated to possible adopted measures,
when appropriate, related to the results obtained shall be available regarding:
I assembly and qualification of equipment;
II analytical apparatus and calibration;
III maintenance, cleaning and sanitation;
IV - personnel, including qualification, training, uniforms and hygiene;
V environmental monitoring;
VI control of plagues;
VII claims;
VIII collections; and
IX returns.
Article 228. There shall be Standard Operational Procedures and logs for the receipt of raw material
and primary packing material and printed material.
Article 229. Registries of receipts shall include, at least:
I name of the material described in the delivery note and in the containers;
II internal denomination and/or code of the material;
III date of receipt;
IV - suppliers name and manufacturers name;
V batch or the manufacturer reference number;
VI total amount and the number of recipients received;
VII number given to the batch after receipt; and
VIII any relevant comment (for instance, the state of the containers).

Article 230. There shall be Standard Operational Procedure for the internal identification of the
products warehoused in quarantine and released (raw materials, packing materials and other
materials).
Article 231. Standard Operational Procedure shall be available for each instrument and equipment
(for instance, use, calibration, cleaning, maintenance) and used next to the equipment.
Article 232. There shall be Standard Operational Procedure for sampling and it shall be defined the
responsible area and the people appointed for the samples collection.
Article 233. Sampling instructions shall include:
I sampling method and plan;
II equipment to be used;
III any precautions to be observed to avoid contamination of the material or any risks to quality;
IV - amount(s) of sample(s) to be collected;
V directions for any necessary sample breakdown;

VI type of container to be used in sample conditioning, labeling, as well as if the sampling


procedure
shall be carried out in conditions of asepsis or otherwise; and

VII - any precautions to be observed, mainly regarding sampling of sterile or hazardous


materials.
Article 234. There shall be a Standard Operating Procedure describing the details of the batch
numbering system, aiming at making sure each batch of intermediate, bulk or finished products is
identified with a specific batch number.
Article 235. The Standard Operating Procedure providing for the batches numbering shall ensure
traceability during all the stages of production, including packaging.
Article 236. The Standard Operating Procedure for batch numbering shall assure that each batch
number will not used more than once, which also applies to reprocessing.
Sole Paragraph. The assignment of a batch number shall be immediately logged.
Article 237. There shall be written procedures regarding the control tests carried out in the materials
and products, in the different stages of production, describing the methods and equipment to be
used.
Sole Paragraph. Tests performed shall be recorded.

Article 238. Analysis records shall include at least the following information:
I - name of the material or product and, as applicable, pharmaceutical form;
II - batch number and, whenever appropriate, the manufacturer and/or supplier;

III - references to the relevant specifications and test procedures;


IV - test results, including notes and calculations, as well as references to any specifications
(limits);
V - date(s) and number(s) of the trial(s) reference;
VI - identification of the people who performed the trials;
VII - identification of the people who verified trials and calculations; and
VIII - statement of approval or rejection (or any other decision), dated and signed by the person in
charge.
Article 239. Written procedures shall be available regarding the approval or rejection of materials
and products and, particularly, regarding the release for sale of the finished product by the person in
charge.
Article 240. Distribution records of each batch of a product shall be maintained so as to, for
example, facilitate any recalls of that batch, as necessary.
Article 241. It shall be kept records of main and critical equipment, such as qualification,
calibration, maintenance, cleaning or repairs, including data and identification of the people
involved in such operations.
Article 242. Records of equipment usage and of the areas where the products are being processed
shall be logged in chronological order.
Article 243. There shall be written procedures assigning the responsibility for cleaning and
sanitation, and describing in detail the frequency, the methods, equipment and materials to be used
in cleaning, as well as the facilities and equipment to be cleaned.
Article 244. It shall be available procedures for computer systems, defining security rules
(users/passwords), systems maintenance and informational infrastructure, management of
information technology deviations, data recovery and backup.
CHAPTER XVI
GOOD
MANUFACTURING
PRACTICES

Article 245. Production operations shall comply with the Standard Operating Procedures, issued,
clearly defined, approved and compliant to the approved registration, aiming at manufacturing
products within the required quality standards.
Item I
General
Article 246. Handling of materials and products, such as receiving and cleaning, quarantine,
sampling, storage, labeling, purging, processing, packaging and distribution, shall be entirely done
in accordance with the written procedures or directions and, when necessary, recorded.
Article 247. Any diversion from the directions or procedures shall be avoided.
Sole Paragraph. In case they occur, however, diversions shall be authorized and approved in writing
by a person assigned by the Quality Assurance, with participation of Quality Control, as applicable.
Article 248. Verifications about performance and reconciliation of quantities shall be carried out to
assure there are no discrepancies beyond the acceptable limits.
Article 249. Operations with distinct products shall not be carried out at the same time or
subsequently in the same room or area, unless there is no risk of cross contamination or
intermingling.
Article 250. During the process, all the materials, containers with bulk, equipment and packaging
lines and rooms used shall be identified with the indication of the product or material being
processed, its concentration (if applicable) and the batch number.
1st This indication shall mention the stage of production.
2nd When applicable, the name of the product previously processed shall also be recorded.
Article 251. Access to the production facilities shall be restricted to the authorized personnel.
Article 252. Non-pharmaceutical products and those that are not subject to the sanitary surveillance
shall not be produced in areas or with equipment meant to the production of medications.
Article 253. Process controls shall not represent any risk to the product's quality, or risks of cross
contamination or intermingling.
Item II
Prevention of Cross Contamination and Micro-biotic Contamination during Production
Article 254. Whenever powder materials and products are used in the production, special
precautions shall be taken to prevent generation and scattering of dust.

Sole Paragraph. Measures shall be adopted to duly control the air (for example, blowing and
exhaustion of air within the specifications established in advance).
Article 255. Contamination of raw materials or a specific product by another material or product
shall be avoided.
1st The risk of accidental cross contamination arises from the uncontrolled release of dust, gases,
vapors, sprays, or organisms from the materials and products in process, residue on the equipment,
introduction of insects, operators outfits, skin, etc
2nd Risk significance varies according to the type of contaminant and to the contaminated
product.
3rd Among the most hazardous contaminants are the highly sensibilizing materials (e.g.
penicilines, cephalosporines, the carbapenems and other beta-lactamic derivates), the biological
preparations with live organisms, certain hormones, cytotoxic substances and other highly active
materials.
4th Special attention shall also be given to products whose contamination may cause damages to
the users, such as those parentally administered or onto open wounds, products administered in
large doses and/or for long periods of time.
Article 256. The occurrence of cross contamination shall be prevented by means of appropriate
techniques or organizational measures, such as:
I - production in exclusive and closed areas (e.g. penicilines, cephalosporines, the carbapenems, the
other beta-lactamic derivates, the prepared biological preparations with live organisms, certain
hormones, cytotoxic substances and other highly active materials);

II - shift production (separated per time periods) each followed by an appropriate cleaning, in
accordance with a validated procedure. For the products listed on item (a), the principle of work in
shifts is only applicable in exceptional cases, such as accidents or situations of emergency;

III - use of prechambers, pressure and blowing differentials and exhaustion systems;
IV - mitigation of the contamination risk caused by the recirculation or re-entrance of non-treated
air or insufficient treated air;

V - use of protection outfit in the place where the products or materials are handled;
VI - use of validated cleaning and decontamination procedures;
VII - use of "closed systems" during production;
VIII - residue tests; and
IX - use of labels in equipments that indicate the status of cleaning.

Article 257. The effectiveness of the measures adopted to prevent cross contamination shall be
verified periodically.
Sole Paragraph. This verification shall be done in compliance with the Standard Operating
Procedures.
Article 258. The production areas where products subject to contamination by microorganisms are
being processed shall be monitored periodically, for example, monitoring microbiological and
particulate materials, whenever appropriate.
Item III
Production Operations
Article 259. Before the beginning of any production operation, the necessary measures shall be
adopted for the work areas and the equipment to be clean and free of any raw materials, products,
product residue, labels or documents that are not necessary for the new operation to start.
Article 260. All the process controls and environmental controls shall be carried out and logged.
Article 261. Means to indicate failures in equipment or utilities shall be deployed.
Sole Paragraph. Deffective equipment shall be removed from use until their repair.
Article 262. After use, production equipment shall be clean within the established timeframe, in
accordance with detailed procedures.
Sole Paragraph. Clean equipment shall be warehoused in a clean and dry place, so as to prevent
contamination.
Article 263. Time limits shall be defined for how long the equipment and/or container may remain
unclean before the cleaning procedure is carried out and between the clean-up and a new utilization.
Sole Paragraph. The time limits shall be based on validation data.
Article 264. Containers used for bottling shall be clean before the operation.
Sole Paragraph. Special care shall be taken to prevent and remove any contaminants, such as,
fragments of glass and particles of metal.
Article 265. Any significant diversion of the expected performance shall be investigated and
recorded.
Article 266. It shall be ensured that piping and other equipment used for product conveying from
one area to the other are correctly connected.
Article 267. The piping systems used to convey purified water or water for injectables, and
whenever appropriate, other types of piping systems, shall be sanitized and maintained in

accordance with written procedures that determine the limits of microbiotic contamination and the
measures to be adopted in case of contamination.
Article 268. Equipment and instruments used in the processes of measurement, weighing, logging
and controls shall be submitted to maintenance and calibration at pre-established intervals, and the
logs of these operations shall be maintained.
1st In order to ensure satisfactory operation, the instruments shall be verified on a daily basis or
before being used for analytical tests.
2nd Calibration, maintenance and future calibration dates shall be clearly established and recorded,
preferably on a sticker attached to the instrument or equipment.
Article 269. Repair and maintenance operations shall not represent any risk to the product's quality.
Item IV
Packaging Operations
Article 270. Upon scheduling packaging operations, there shall be procedures to minimize the risks
of cross contamination, of intermingling or replacements.
Sole Paragraph. Different products shall not be packed next to each other, unless there is a physical
partition or an alternative system to ensure an equivalent safety.
Article 271. Before beginning packaging operations, measures shall be taken to make sure the work
area, the packaging lines, the printers and other equipment are clean and free of any products,
materials or documents used earlier and that are not necessary for the current operation.
1st Clearance of the line shall be carried out in accordance with the procedures and the checklist.
2nd Inspection shall be registered.
Article 272. The name and the batch number of the product in process shall be displayed in each
stage of packaging or in the packaging line.
Article 273. The bottling and capping stages shall be immediately followed by the labeling stage.
Sole Paragraph. If the provisions of the head hereof are not possible, the due procedures shall be
applied to make sure no mislabeling or intermingling occurs.
Article 274. The correct execution of the printing operations shall be verified and recorded, as
carried out separately or during progress of the packaging process.
Sole Paragraph. Thorough attention shall be given to manual printing, which shall be verified
regularly.

Article 275. In order to prevent intermingling/replacement, there shall be special care when using
loose labels or when large volumes of printing are done outside the packaging line, as well as when
manual packaging operations are adopted.
1st Preference shall be given to roll feeding of labels as opposed to lose labels, to prevent
confusion.
2nd Verification in line of all the labels by electronic means may be useful to prevent
intermingling; however, check-ups shall occur to make sure any electronic code scanners, label
counters or similar devices are working correctly.
3rd Whenever the labels are attached manually, process controls with shall be carried out more
frequently.
Article 276. The information printed or stamped embossed in the packaging materials, they shall be
sharp, wear-resistant and abrasion-resistant.
Article 277. In-line inspection of the product during packaging shall comprise regularly, at least the
following verifications:
I - general appearance of the packages;
II - if the packages are complete;

III - if the correct products and packaging materials are being used;
IV - if the printed matter is correct; and
V - the correct functioning of the packaging line monitors.
Sole Paragraph. The samples removed from the packaging line for in-line inspection shall not return
to the packaging process without due assessment.
Article 278. The products involved in abnormal occurrences during the process of packaging shall
only be re-introduced after being submitted to inspection, investigation and approval by the person
in charge.
Sole Paragraph. Detailed records of these operations shall be maintained.
Article 279. Any significant or uncommon discrepancy observed during reconciliation of the
quantity of bulk materials, printed packaging materials and the number of units packed, shall be
investigated and reasonably justified before batch is released.
Article 280. After completion of each operation, all the packaging materials coded with the batch
number and not used shall be destroyed, whereas the destruction process shall be recorded.

Sole Paragraph. In order for the non-coded printed material to be returned to stock, written
procedures shall be complied with.
CHAPTER XVII
GOOD QUALITY CONTROL PRACTICES
Article 281. Quality Control is in charge of the activities related to sampling, specifications and
tests, as well as to the organization, documentation and process of clearance that ensure the tests are
performed and the materials and finished products are not approved until its quality is deemed
satisfactory.
Sole Paragraph. Quality Control shall not restrict itself to laboratory operations, yet participate and
be involved in any decisions that may relate to the product's quality.
Article 282. Independence of Quality Control regarding production is essential.
Article 283. Each manufacturer (entitled to a manufacture authorization) shall have a Quality
Control group.
1st Quality Control Group shall be under responsibility of a duly qualified and experienced person,
who has on or more control laboratories available for use.
2nd Suitable resources shall be available to make sure all Quality Control activities are carried out
with effectiveness and reliability.
3rd The basic requirements for Quality Control are the following:

I - suitable facilities, well-trained personnel and approved procedures shall be available for the
sampling, inspection and analysis of raw materials, packaging materials, intermediate products,
bulk and finished products. - Whenever necessary, there shall be procedures approved for
environmental monitoring;

II - samples of raw materials, packaging materials, intermediate products, bulk and finished
products shall be collected by means of procedures approved and staff qualified by Quality Control;
III - the necessary qualification and validations related to Quality Control shall be carried out;
IV - records (manual or electronic) shall be done evidencing that all the sampling, inspection and
test procedures were indeed carried out and any diversions were duly recorded and investigated;

V - the finished products shall have a qualitative and quantitative composition in accordance with
the descriptions of the records; the components shall have the required purity, and be warehoused in
suitable containers and duly labeled;

VI - the results of the analyses carried out in the materials and intermediate products, bulk and
finished products shall be recorded;

VII - no batch of product shall be approved before assessment of compliance with the
specifications contained in the records by persons assigned thereto; and

VIII - enough samples of raw materials and products shall be withheld to allow future assessments;
the withheld product shall be kept in its definitive package, unless the package is exceptionally
large.
Article 284. Other assignments of Quality Control are to establish, validate and implement all
Quality Control procedures, to assess, maintain and store the reference standards, to ensure the
correct labeling of the reagents, standards and other materials of its use, to ensure the stability of the
active ingredients and medicaments is monitored, to participate in the investigation of complaints
related to the product's quality and to participate of the environmental monitoring.
Sole Paragraph. All these operations shall be carried out in compliance with written and, whenever
necessary, registered procedures.
Article 285. The Quality Control staff shall have access to the production areas for sampling and
investigation.
Item I
Control of Raw Materials and Intermediate, Bulk and Finished Products
Article 286. Every trial shall follow written and approved procedures.
Sole Paragraph. Results shall be verified by the person in charge before the materials or products
are released or rejected.
Article 287. Samples shall represent the batch of material from which they were removed, in
accordance with written and approved procedures.
Article 288. Sampling shall be carried out so as to prevent the occurrence of contamination or other
adverse effects on the sampled product's quality.
Sole Paragraph. Sampled containers shall be identified and carefully sealed after sampling.
Article 289. During sampling, care shall be taken to prevent contaminations or intermingling of the
sampled materials.
1st All equipment used in sampling and which are in contact with any materials shall be cleaned
thereafter.
2nd Certain particularly hazardous or powerful require special precautions.
Article 290. Equipment used in sampling shall be clean and, if necessary, sterilized and warehoused
separately from other lab equipment.
Article 291. Each container holding samples shall be identified and show the following information:

I - name of the sampled material;


II batch number;

III - number of the container from which the sample was removed;
IV - sample number;
V - signature of the person in charge of the collection; and
VI - sampling date.
Article 292. The results out of specification, obtained during the tests with materials or products
shall be investigated in accordance with an approved procedure.
Sole Paragraph. The investigations shall be completed, the corrective and preventive measures
adopted and the records maintained.
Item II
Necessary Trials on Raw Materials and Packaging Materials
Article 293. Before the raw materials and the packaging materials are released for use, the person in
charge of Quality Control shall ensure that they were tested in regards to compliance with the
specifications.
Article 294. Identification tests with the samples removed from any raw-material containers shall be
performed.
Article 295. Sampling of only one part of the volumes is allowed, whenever a vendor qualification
process has been established to make sure no batch of raw materials is unduly labeled.
1st Qualification process shall take into consideration at least the following aspects:

I - nature and classification of the manufacturer and of the supplier, and its level of compliance
with the Good Manufacture Practices requirements;

II - the manufacturer's Quality Assurance system for raw materials;


III - the conditions under which raw materials are produced and controlled; and
IV - nature of raw materials and of the medicament in which they shall be used.
2nd With such qualification, it is possible for the test to be exempt of identification in samples
removed from each raw-material container in the following cases:
I - raw materials originated from a single-product plant; or

II - raw materials acquired directly from the manufacturer, or in containers sealed at the
manufacturer's facilities, which have a reliable history and undergo regular quality audits by the
manufacturer's Quality Assurance system.
3rd The exemption foreseen in the previous paragraph does not apply in the following cases:

I - raw materials supplied by sub-vendors, such as importers and distributors, whenever the
manufacturer is not known or audited by the manufacturer of the medication;

II - fractioned raw materials; and


III - raw materials used for parental products.
Article 296. Each batch of material with printed packages shall be examined before usage.
Article 297. In substitution to the performance of Quality Control tests, the manufacturer may
accept the certificate of assessment issued by the supplier, provided its reliability is established by
means of periodic assessment of the results presented and of audits in its facilities, which does not
exclude the required identification test.
1st The certificates issued by the supplier shall be the original forms with assured authenticity.
2nd The certificates shall contain the following information:
I - identification of the supplier, signature of the employee in charge;
II - name and batch number of the material tested;

III - description of the specifications and of the methods used; and


IV - description of the test results and the date of performance thereof.
Item III
Control in Process
Article 298. Process control records shall be maintained, which shall be part of the batch's
documentation.
Item IV
Finished Products
Article 299. In order the batches are released, compliance with the established specifications, by
means of laboratory tests, shall be assured.
Article 300. Products that do not comply with the established specifications shall be rejected.

Item V
Reference
Samples
Article 301. The samples withheld from each batch of finished products shall be kept for at least 12
(twelve) months after expiry, except for Large Volume Parental Solutions (SPGV), which shall be
conserved for at least 30 (thirty) days after expiry.
1st The finished products shall be maintained in their definitive packages and warehoused under
the recommended conditions.
2nd If the product is packed in large packages, samples may be exceptionally warehoused in
smaller containers with the same characteristics and under the recommended conditions.
3rd Samples of active substances shall be withheld for at least one year after expiry of the term of
effectiveness of the finished products that originated them.
4th Samples of other raw materials (excipients), e.g. ketosolvents, gases and water, shall be
withheld for a minimum period of two years after its respective term of effectiveness, if so allowed
by the respective stability surveys carried out by the raw materials manufacturer.
5th Quantities of withheld samples of materials and products shall be enough to allow the
performance of at least two full analyses.
Item VI
Stability
Study
Article 302. Quality Control shall assess the quality and stability of the finished products and,
whenever necessary, of the raw materials, of the intermediate and bulk products as well.
Article 303. Dates and specifications of expiry shall be established based on the stability tests
related to storage conditions.
Article 304. A written program of stability surveys shall be developed and implemented, including
the following elements:
I - full description of the products involved in the survey;

II - all the parameters of methods and tests, which shall describe the procedures of the strength,
pureness, physical characteristics, and microbiological test (when applicable), as well as the
documented evidences that the tests were performed are indicators of the product's stability;

III

- forecast of the inclusion of a sufficient number batches;

IV - schedule of test for each product;

V - directions on special warehousing conditions;


VI - directions on the suitable withholding of samples; and
VII - a summary of all the data obtained, including the assessment and the conclusions of the
survey.
Article 305. The stability of a product shall be determined before its trading, and it shall be repeated
after any significant changes of the production process, equipments, packaging materials and other
inputs that may impact the product's stability.
TITLE III
STERILE PRODUCTS
Article 306. The herein presented guidelines do not supersede any previous section, but reinforce
the specific points on sterile prepared manufacturing, with the purpose to minimize the
contamination risks by feasible or non-feasible particles or by pyrogenic substances.
CHAPTER I
GENERAL CONSIDERATIONS
Article 307. The production of sterile substances shall be carried out in clean areas, where the
admission of personnel and materials shall be done through prechambers.
Sole Paragraph. Such areas shall be kept within the proper cleanliness standards and shall have
ventilation systems which use evidenced efficiency filters.
Article 308. The several operations involved in the preparation of materials (e.g. containers and
caps), in product preparation, bottling and sterilization shall be carried out in segregated areas inside
the cleaned area.
Article 309. The manufacturing operations are divided into two categories: the first, where the
products are terminally sterilized and the second, where part or all process steps are aseptically
conducted.
CHAPTER II
QUALITY CONTROL
Article 310. The samples collected for the sterility test shall represent the full batch and/or subbatch, whereas special attention shall be given to the portions of the batch that represent larger risk
of contamination, such as:

I - products that have passed through aseptic bottling process - the samples shall include the initial
and final containers of the lot, and also after any significant interruption of work;

II - products that have been heat sterilized in their definitive package - the samples shall include
containers of the potentially colder zones of each load.
Article 311. The sterility test carried out with the finished product shall be considered merely as one
of the last control measures used to ensure the product's sterility.
Article 312. The finished goods sterility is ensured by validation of sterilization cycle in case of the
terminally sterilized products, and through simulation with culture media for aseptically
manufactured products.
1st Batch documentation and the registries of environmental monitoring shall be examined jointly
with the sterility test results.
2nd The procedure of sterility test shall be validated for each product.
3rd Pharmacopoeic methods shall be used for validation and performance of sterility test.
Article 313. Injectable products, injectable water, intermediate products and finished products shall
be monitored regarding endotoxines, using a pharmacopoeic method that has been validated for
each product.
1st For high volume parental solutions, such monitoring on water or intermediates shall also be
done, in addition to the tests required by the approved background paper of finished product.
2nd When a sample fails in a test, the cause of disapproval shall be investigated and the corrective
actions shall be taken, when necessary.
Article 314. The batches that were not approved in the initial sterility test cannot be approved based
on a second test, except if an investigation carried out and the result shows clearly that the initial
test was not valid.
Sole Paragraph. The investigation shall comprise, among other aspects, the type of microorganism
found, the records on the environmental conditions and on the batch processing, as well as the
laboratory records and procedures used in the initial test.
CHAPTER III
SANITATION
Article 315. Sanitation of the clean areas is a particularly important aspect as to the manufacture of
sterile products.
1st Such areas shall be often cleaned and sanitized according to a specific program approved by
Quality Assurance.
2nd These areas shall be regularly monitored for detection of resistant microorganisms arising.

3rd In view of the limited efficiency of ultraviolet radiation, it shall not be used as substitute in
chemical disinfection operations.
Article 316. The disinfectant and detergents shall be monitored in order to detect possible microbial
contamination; its efficacy shall be evidenced; the dilutions shall be kept in previously cleaned
containers and should not be stored for long periods of time, unless they are sterilized.
1st The partially emptied containers shall not be filled.
2nd Disinfectants and detergents used in the A and B level areas shall be sterilized before their use
or have their sterility proven.
Article 317. A microbiological control of the different classes of cleaned areas during the operation
shall be performed.
1st When aseptic operations are carried out, the monitoring shall be frequent and the methods,
such as settlement plates, air and surface volumetric sampling (i.e.: swab and contact plates) shall
be applied.
2nd The areas shall not be contaminated by the sampling methods used.
3rd Monitoring results shall be reviewed for the purposes of release of the finished product.
4th Surfaces and personnel shall be monitored after accomplishment of critical operations.
Article 318. Limits of alert and action upon detection of microbiological contamination and also for
monitoring of air quality trend inside the facilities shall be established.
Sole Paragraph. The limits expressed in colony-forming units (CFU) for microbiological monitoring
of cleaned areas under operation are found outlined in Table 1 provided in the ANNEX.
CHAPTER IV
PRODUCTION OF STERILE
SUBSTANCES
Article 319. The cleaned areas for sterile products manufacturing are classified according to its
environmental conditions.
1st Each step of production requires a suitable "runtime" environmental condition, to minimize the
risk of microbiological or particle contamination of the product or of the materials used.
2nd To reach the "in operation" conditions, these areas shall be drawn to meet certain air purity
levels under "at rest" condition. The "at rest" condition is defined as that where the facility is
finished, the production equipment is installed and operating, but there are no people present. The
"in operation" condition is defined as that in which the area is running for a established operation
and with a specified number of people present.

3rd The cleaned areas used for sterile products manufacturing are classified in four different
grades, as follows:

1 A Level: high operational risk zone, for example, bottling and aseptic connections. Normally
these operations shall be performed under unidirectional flow. The unidirectional flow systems shall
provide a homogeneous air speed of approximately 0.45m/s 20% in the work position;
II B Level: in surrounding areas of level A, for aseptic preparation and bottling; and
III C" and "D" Levels: cleaned areas where the less critical steps of sterile products
manufacturing are performed.
4th Air classification for the four levels is found on Table 2 of the ANNEX.
5th To reach B, C and D levels, the number of air exchanges shall be suitable to the size of the
room, to equipment therein, and to the number of people working therein.
6th The total number of air exchanges in the area shall be at least 20 events per hour in a room
with standard and suitable air flow, and with high effectiveness filters for the due retention of
particles (HEPA - high efficiency particle air filters).
7th The different particle classification systems for clean areas are shown on Table 3 of the
ANNEX.
Article 320. The at rest condition described on Table 2 shall be reached once the operations are
completed, in the absence of personnel and after a short period of recovery.
1st The "in operation" condition for Class A shall be maintained within the intermediate product
surroundings whenever the product is exposed to environment.
2nd There may be difficulties on demonstrating compliance with classification of air in bottling
point during this operation due to formation of particles/droplets resulting from the product itself.
Article 321. Limits of alert and action shall be established for both microbiological and particle
monitoring.
Sole Paragraph. If the limits are exceeded, corrective actions shall be taken, according to what is
described in the operating procedures.
Article 322. The levels of each production area are specified on the following items and shall be
selected by the manufacturer, based on the nature of the process and on the corresponding
validations.
Item I
Ultimately Sterilized Products

Article 323. The materials and most of the products shall be prepared in an environment classified
as at least D level so that a low microbiological and particle count is achieved, as suitable for
filtering and sterilizing.
Sole Paragraph. When the product is subjected to a high microbial contamination risk (i.e.: due to
being highly susceptible to microbial growth, requires to be kept by a long period prior to
sterilization, or it is not processed in closed containers), the preparation shall be performed in a C
level environment.
Article 324. Bottling of terminally sterilized products shall be performed in a minimum C level
environment.
Sole Paragraph. When the product is subject to a risk of contamination by the environment (i.e.:
slow bottling process, containers with a big opening or exposing of these for more than a few
seconds before closing) the bottling shall be carried out in an A level environment, surrounded by, at
least, an level area.
Article 325. Preparation of other sterile products, i.e., salves, creams, suspensions and emulsions, as
well as filling of the respective containers shall be conducted, generally, in a C level environment,
before the final sterilization.
Item II
Aseptic Preparation
Article 326. The materials shall be handled in, at least, a D level environment after washing.
Article Handling of sterile raw material and other materials, unless they are subjected to
sterilization or sterilizing filtration, shall be performed in an A level environment surrounded by a B
level environment.
Article 328. The preparation of solutions sterilized by filtering during the process shall be carried
out in an area classified as at least C level.
Sole Paragraph. If solutions are not sterilized by filtering, the preparation of materials and products
shall be done in an A level environment, surrounded by a B level environment.
Article 329. Handling and bottling of aseptically prepared products, as well as the handling of
previously sterilized equipment shall be performed in an A level environment, surrounded by a B
level environment.
Article 330. Transfer of partially closed containers, such as those used in lyophilization (freezedrying), shall be carried out in an A level environment surrounded by a B level environment before
being completely closed, or the transfer shall occur in closed trays, in a B level environment.
Article 331. Preparation and bottling of sterile salves, creams, suspensions and emulsions shall be
performed in an A level environment, surrounded by a B level environment, when the product is
exposed and then filtered.

Item III
Production
Article 332. Some precautions shall be taken in order to minimize the contamination during all
production steps, including those before sterilization.
Article 333. Preparations containing live microorganisms cannot be produced or bottled in the areas
used for production of other medications.
Sole Paragraph. The vaccines made of inactivated microorganisms or with bacterial extract can be
bottled, after its inactivation, at the same facilities of other drugs, since the inactivation and
cleanliness procedures are validated.
Article 334. Validation of the aseptic processes shall comprise their simulation by using means of
culture.
1st Culture media form adopted shall be generally equivalent to the pharmaceutical form of the
product.
The simulation process shall simulate in the most possible true form the routine operations,
including all subsequent critical steps.
3rd The conditions of the previous case shall be considered in the simulation.
4th The simulation shall be repeated in regular intervals and whenever a significant change on the
equipment and processes occurs.
5th The number of containers used in a simulation with means of culture shall be enough to ensure
the assessment's reliability.
6th For small lots, the number of containers used in the simulation shall be at least equal to the
product lot size.
Article 335. Precautions shall be taken in order to the validation processes do not negatively affect
the production processes.
Article 336. Sources of water supply, water treatment equipment and the treated water shall be
regularly monitored for presence of chemical and biological contaminants and, when applicable, the
endotoxin control shall be performed, with purpose to such water meets the suitable specifications
for its usage.
Sole Paragraph. Logs of the monitoring results and of the measures adopted in events of diversion
shall be maintained.
Article 337. The activities developed in cleaned areas shall be the minimum possible, mainly when
aseptic operations are being carried out.

1st The movement of people shall be methodic and controlled, with purpose to avoid an excessive
detachment of particles and microorganisms.
2nd Temperature and humidity of environment cannot be uncomfortably high due to nature of the
uniforms used.
Article 338. The presence of containers and materials that generate particles in the cleaned areas
shall be reduced to the minimum and completely avoided when an aseptic process is being carried
out.
Article 339. After the final cleanliness or sterilization process, the handling of components, bulk
product containers and equipment shall be performed in such way to avoid them to become
contaminated again.
Sole Paragraph. Each processing step of components, bulk product containers and equipment shall
be properly identified.
Article 340. The time-out between the washing, drying and sterilization of components, bulk
product containers and equipment, as well as the interval between the sterilization and use, shall be
the shortest possible and it shall be subjected to a time limit appropriated to the validated storage
conditions.
Article 341. The time between the beginning of preparation of a specific solution and its sterilizing
shall be the shortest possible.
Sole Paragraph. A maximum permissible time for each product shall be established, taking into
consideration the product composition and the recommended storage method.
Article 342. Every gas in direct contact with the product, such as those meant to assist in the
filtering or solution bottling processes, shall be submitted to the sterilizing filters.
Sole Paragraph. The integrity of critical gas and air filters shall be confirmed after use.
Article 343. The bioburden of products shall be monitored before sterilization.
Sole Paragraph. A maximum limit of contamination prior to sterilization shall be established, which
are related with the efficiency of the method that will be used and with the contamination risk by
pyrogenic substances.
Article 344. All the solutions, especially the large volume Parental Solutions shall be submitted to
filtering in order to reduce their bioburden, if possible immediately before its filling process.
Article 345. When aqueous solutions are placed in sealed containers, the pressure compensation
orifices shall be protected, for example, with hydrophobic filters that block the passage of
microorganisms.

Article 346. The components, bulk product containers, equipment and/or any other items needed in
the cleaned area where aseptic activities are being developed shall be sterilized and, whenever
possible, transferred to the cleaned areas through dual port sterilizers built-in in the wall.
Sole Paragraph. Other procedures used to avoid the entrance of contaminants into the cleaned area
can be accepted in some circumstances (for example, triple casing).
Article 347. Any new procedure of manufacturing shall be validated to evidence its efficacy.
Sole Paragraph. Validation shall be repeated in regular intervals or when significant changes in
process or equipment are made.
CHAPTER V
STERILIZATION
Article 348. When possible, products shall be preferably sterilized by heat inside its final container.
Sole Paragraph. When the heat sterilization method is not possible due to instability of formulation,
an alternative method shall be used preceding filtration and/or aseptic process.
Article 349. Sterilizing may occur upon application of dry or moist heat, ionizing radiation, other
gaseous sterilizing agents or sterilizing filters with subsequent aseptic filling of the sterile definitive
containers.
Sole Paragraph. Each method has its particular applications and limitations. When possible and
feasible, the selection of method shall be sterilization by heating.
Article 350. Microbiological contamination of raw materials shall be the least possible, and their
bio-load shall be monitored whenever such need is indicated.
Article 351. All sterilization processes shall be validated, considering the different loads.
1st The sterilization process shall be aligned with that stated in the technical report of the Product
Log.
2nd Special attention shall be given when sterilization methods which are not in accordance with
those described in pharmacopoeias or in other official compendia, as well as when such methods are
used for sterilization of products other than simple aqueous or oily solutions.
Article 352. Before the adoption of any sterilizing process, its effectiveness and its adequacy shall
be proven by means of physical tests (including distribution and heat penetration tests) and by the
use of biological indicators, in the sense that the desired sterilization conditions are achieved in all
the areas of each type of load to be processed.
1st The process shall be submitted to periodic revalidation, at least once a year, and whenever
significant changes in the load to be sterilized or in the equipment occur.

2nd Results shall be logged.


Article 353. For a effective sterilization, all material shall be subjected to the required treatment and
the process shall be planned, in order to ensure the effective sterilization.
Article 354. The biological indicators shall be considered only as an additional method for
sterilization processes monitoring. They shall be warehoused and used according to manufacturer
instructions and its quality shall be checked by positive controls. If f utilized, there shall be rigorous
precautions to prevent microbiotic contamination therefrom.
Article 355. Clarified means to distinguish the products and materials that have been sterilized from
those that haven't shall be established.
1st Each container, tray or other kind of product or material conveyor shall be visibly identified
with the name of the material or product, its lot number and indication if they were sterilized or not.
2nd Whenever appropriate, indicators may be used, such as autoclave straps, to indicate if a
specific batch (or sub-batch) was submitted to the sterilizing process or otherwise; however, these
indicators do not provide reliable information that evidence the batch was indeed sterilized.
Article 356. Records of each sterilization cycle shall be maintained.
Sole Paragraph. Such records shall be approved as part of batch releasing procedure.
Item I
Ultimate Sterilization
Subitem I
Heat Sterilization
Article 357. Each heat sterilization cycle shall be registered with proper equipment, with suitable
reliability and accuracy, (for example: a time/temperature chart with sufficiently wide scale).
1st The temperature shall be registered from a probe installed at the most cold point of the
sterilization chamber, such point determined during the qualification process.
2nd The temperature shall be verified, preferably against a second stand-alone temperature sensor,
located at the same position.
3rd The sterilization cycle records shall be comprised in the lot documentation.
4th Chemical and biological indicators may also be used, but it should not supersede the physical
controls.
Article 358. Sufficient time shall be given in order to the totality of load reaches the necessary
temperature before the sterilization time measurements are initiated.
Sole Paragraph. Such time shall be determined for each type of load to be processed.

Article 359. After the maximum temperature phase of heat sterilization cycle, the required
precautions to avoid the contamination of sterilized load shall be taken, during the cooling phase.
Sole Paragraph. Any fluid or gas used in the cooling phase that is in direct contact with the product
or material shall not be a source of microbiological contamination.
Subitem II
Moist Heat Sterilizing
Article 360. Moist heat sterilizing is indicated only in case of materials permeable to steam and
watery solutions.
1st Temperature and pressure shall be used to monitor the process.
2nd The temperature recorder probe shall be independent from the probe used by the autoclave
controller and a temperature indicator shall exist, whose reading during the sterilization process
shall be routinely checked through comparison with values obtained from chart.
3rd In case of autoclaves that have a drain in the lower part of sterilization chamber, it is also
necessary to record the temperature at this position, during the whole sterilization process.
4th When a vacuum phase is part of the sterilization cycle, periodic controls of air-tightness of
chamber shall be performed.
Article 361. The materials to be sterilized (when they are not inside sealed containers) shall be
wrapped up with materials that allow the removal of air and penetration of vapor and also that avoid
the recontamination after sterilization.
Sole Paragraph. All parts of autoclave load shall be in contact with the saturated vapor or water, at
the required temperature and during the established time.
Article 362. It shall be ensured that the vapor used in sterilization is of proper quality to the process
and also that it does not contain additives in amounts that could cause contamination of product or
equipment.
Subitem III
Dry Heat Sterilizing
Article 363. The dry-heat sterilization can be suitable for non-aqueous liquids or powdered
products.
1st The dry-heat sterilization process shall include the forced air circulation inside the sterilization
chamber and the positive pressure maintenance, in order to avoid the entry of non-sterile air.
2nd If air is introduced into the chamber, it shall be filtered through a microbiological retention
filter.

3th When the dry-heat sterilization process is also used for pyrogenics removal, tests using
endotoxins shall be performed as part of validation.
Subitem IV
Radiation Sterilizing
Article 364. The radiation sterilization is mainly used with heat-sensitive materials and products.
On the other hand, many drugs and some packaging materials are sensitive to radiation.
1st Therefore, this method shall be applied only when there are no harmful effects to the product,
evidenced by experiments.
2nd The ultraviolet radiation is a non-acceptable sterilization method.
Article 365. If the radiation sterilization is carried out by third-party contract, the manufacturer is
responsible for ensuring that the requirements predicted in above item are met and that the
sterilization process is validated.
Sole Paragraph. The responsibilities of radiation plant operator (i.e.: correct dosing usage) shall be
specified.
Article 366. During the sterilization process, the radiation doses used shall be measured.
1st Dose-rangers Shall be used that are independent from the applied dose and that indicate the
actual quantity of radiation doses received by the product.
2nd The dosimeters shall be included on load in sufficient number and so close to each other that
allow ensuring that is always a dosimeter in the radiation chamber.
3rd Whenever plastic dose-rangers are used, these shall also be used within the time limit
established by its calibration.
4th The absorption values reading from the dose-rangers shall be obtained immediately after a
exposition to the radiation.
5th Biological indicators can only be used as additional control mean.
6th Color discs sensitive to radiation can be used to distinguish the packages that were subjected to
radiation, from those that were not; such discs cannot be considered as indicator of sterility
assurance.
7th All information obtained during the process shall be registered in the batch documentation.
Article 367. The effects of density variations of the material to be sterilized shall be considered in
the validation of the sterilizing process.
Article 368. Procedures for handling materials shall ensure there is no possibility of intermingling
between the radiated and non-radiated products.

Sole Paragraph. Each packaging shall have a radiation-sensitive indicator that identifies those that
have been irradiated.
Article 369. Total radiation dose shall be applied for a predetermined period of time.
Gas and Fuming
Sterilizing
Article 370. The methods of sterilizing with gases or fumes shall only be used when no other
method is available.
Article 371. Several gases and fumes can be used for sterilization (i.e.: ethylene oxide, hydrogen
peroxide vapors).
Sole Paragraph. The ethylene oxide shall be used only when there is no other applicable method.
Article 372. During the process validation, it shall be evidenced that there is no harmful effects for
product and that the ventilation time is sufficient for the gas and reactive products to be below the
limits considered as acceptable for the product. Such limits shall be incorporated to specifications.
Article 373. Direct contact between the gas and the microorganisms shall be assured.
1st Precautions shall be adopted in order to avoid the presence of organisms that could be
contained in materials such as dried proteins and crystals.
2nd The nature and quantity of packaging materials can significantly affect the process.
Article 374. Before being subject to the gas action, materials shall reach and maintain balance
between temperature and humidity required by the process.
Sole Paragraph. The time spent in this process shall be taken into consideration in order to minimize
the time prior to sterilization.
Article 375. Each sterilizing cycle shall be monitored with the suitable biological indicators, in due
quantity, distributed throughout the entire load.
Sole Paragraph. Such records shall be comprised of the lot documentation.
Article 376. The biological indicators shall be conserved and used, in accordance with the
manufacturer's instructions, and its performance shall be verified by means of positive controls.
Article 377. For each sterilization cycle, records of the sterilization cycle time, pressure,
temperature and humidity inside the chamber during the process and also of the gas used
concentration shall be kept.

1st Pressure and temperature shall be recorded in chart during the each and
every cycle. 2nd Such records shall be comprised of the batch documentation.
Article 378. After sterilizing, load shall be stored in a controlled fashion, under good ventilation
conditions, so that the residual gas and the reactive products therein decay to acceptable levels.
Sole Paragraph. This process shall be validated.
Item II
Aseptic Process and Filter Sterilizing
Article 379. The aseptic process shall maintain the sterility of the product that is prepared with the
components, which were sterilized by one of the above mentioned methods.
Sole Paragraph. The operation conditions shall prevent the microbial contamination.
Article 380. During the aseptic process, special attention shall be given to the following items, in
order to maintain the sterility of components and products:
I environment;
II personnel;
III critical surfaces;

IV - procedures for sterilizing and for transfer of containers/covers;


V - maximum storage period of product before bottling; and
VI sterilizing filter.
Article 381. Some solutions and fluids that cannot be sterilized inside the definitive containers may
be filtered into containers previously sterilized, through filters also previously sterilized (in
accordance with the manufacturer's recommendations), specifying the pore size of 0.2 um (or less),
whereas it is essential that it holds documentation evidencing it was duly submitted to a bacterial
challenge.
Sole Paragraph. The filters may remove bacteria and fungi; however, they might allow in certain
microorganisms (e.g. mycoplasma). The filter shall be validated in order to prove it effectively
sterilizes the product into the actual process conditions, without causing harmful changes to its
composition.
Article 382. Given the potential additional risks of the filtering method as compared to other
sterilizing processes, it is advisable to use redundant sterilizing filters (two in a row) or one
additional filter immediately before the bottling.

Sole Paragraph. Sterilizing filters may be single-layer or double-layer filters.


Article 383. Final sterilizing filtration shall be performed the closest as possible to the filling point.
Article 384. Only lint-free filters shall be used.
Sole Paragraph. Using asbestos filters shall be absolutely excluded.
Article 385. The integrity of the filter shall be verified by an appropriate method, such as the
bubble-point test, diffuse flow test or pressure retention/decline test, immediately after use. It is also
recommended the accomplishment of integrity test of the filter before use.
1st Parameters for the integrity test (wet fluid, gas test, test pressure, test temperature, criterion for
approval etc.) for each specific sterilizing filter there shall be a procedure. These parameters shall
relate to bacteria challenge test carried out earlier, and this relation shall be documented.
2nd In case the product itself is used as the wet fluid, the survey for development integrity test
parameters shall be documented.
Article 386. The integrity of the critical filters shall be confirmed after their use. It shall be
considered critical filters all those destined to filter fluids that enter in direct contact with the
product (i.e., gas and air filters, tank breathe filters). It is also recommended the accomplishment of
an integrity test of the filter before use.
1st The integrity of the other sterilizing filters shall be confirmed in appropriate intervals.
2nd The increasing of integrity monitoring of filters in processes that involve drastic conditions,
such as the air circulation under high temperature shall be taken into consideration.
Article 387. The filtering time as well as all other operating conditions such as temperature,
pressure differentials, batch volume, physical-chemical characteristics, etc., shall have been
considered in the validation of the sterilizing filtering.
1st Any significant differences in the process as related to the parameters considered in the
validation shall be recorded and investigated.
2nd The results of these verifications shall be written down in the lot documentation.
Article 388. The same filter shall not be used for more than one work day, unless such use has been
validated.
Article 389. The filter shall not affect the product by removing its ingredients or adding other
substances.
Item III
Personnel

Article 390. Only the minimum number of people required shall be present in the cleaned areas, that
is, this is particularly important during aseptic processes. If possible, the inspection and controls
shall be performed outside these areas.
Article 391. All employees (including cleaning and maintenance staff) who carry out any activities
in these areas shall receive initial and regular training in the disciplines that are relevant to the
production of sterile products, including reference to personal hygiene issues, basic microbiology
concepts and procedures for the due outfits in clean areas.
Sole Paragraph. If necessary, admission into this area of persons that were not trained will require
specific care as to their supervision.
Article 392. The employees that are participating of activities related to production of animal tissue
substrate or culture of microorganisms different from those used in the manufacturing process in
progress, shall not enter in the sterile products production areas, unless previously established
decontamination procedures are applied.
Article 393. The adoption of high standards of personal hygiene and cleanliness are essential. The
people involved in manufacturing of drugs shall be instructed to communicate to his/her superior,
any changes of his/her health conditions that can contribute to spreading contaminants.
1st It is recommended the realization of periodic health examinations.
2nd The actions to be taken with respect to people that can be posing improper microbiological
risks shall be taken by qualified personnel who are designated for such task.
Article 394. Personal use clothes shall not be brought into the cleaned areas.
1st People who enter in the locker-room of these areas shall already be wearing the factory
standard outfits.
2nd The clothing changing and sanitation processes shall follow written procedures, elaborated to
minimize the contamination of sterile gowning cleaned area, or the conduction of contaminants to
the cleaned area.
Article 395. Pulse watches and jewelry shall not be used in cleaned areas, as well as cosmetic
products that can detach particles.
Article 396. Clothing used shall be proper to process and classification of the cleaned area where
the personnel is currently working.

I D Level: Hair, beard and mustache shall be covered. Protective clothing and closed shoes or
footwear protectors suitable to the area shall be used. Suitable measures shall be taken to avoid any
contamination arising from the external areas.

II

- C Level: Hair, beard and mustache shall be covered. Suitable clothing shall be used, tied
to wrist and with high stand. The clothing shall not release fiber or particles. In addition, closed
shoes or footwear protectors suitable to the area shall be used.
III Levels A/B: A hood that covers the hair entirely shall be worn, beard, mustache and hair tips
shall be placed inside the hood or masked. A face mask shall be worn in order to avoid spreading
sweat drops. Sterilized rubber gloves, without powder, in addition to disinfected or sterilized boots
shall be worn. The pants hem shall be putted into the boots, as well as the sleeves putted into the
gloves. The protective clothing shall not release any fiber or particle and it shall hold the particles
released by the body of who is using it.
Article 397. Personal clothing shall not be brought into the outfit rooms that have access to the B
and C level areas.
Article 398. All the employees working in A and B level rooms shall receive clean and sterilized
outfits at every work shift.
Article 399. Gloves shall be regularly disinfected during the operations, as well as masks and gloves
exchanged in each work session/shift.
Article 400. Clothing used in cleaned areas shall be washed or cleaned, in order to avoid releasing
of contaminants in areas where such clothes are going to be used.
1st It is recommended to have a laundry exclusively intended for this kind of clothing.
2nd Damaged clothing due to usage can increase the risk of particles releasing.
3rd Outfit cleaning and sterilizing operations shall comply with the Standard Operating Procedures
SOP.
4th Use of disposable clothing might be needed.
Item IV
Facilities
Article 401. All facilities, whenever possible, shall be designed in order to avoid the unnecessary
entry of supervision and control personnel.
Sole Paragraph. B level areas shall be designed in order to allow all operations to be observed from
outside.
Article 402. In the cleaned areas, all exposed surfaces shall be flat, impermeable in order to
minimize the deposit or releasing of particles and microorganisms, allowing the repeated
application of cleaning agents and disinfectants, when it is the case.
Article 403. To reduce the dust accumulation and facilitate the cleaning, there shall not exist any
surfaces that cannot be cleaned.

1st The facilities shall have the minimum of saliencies, shelves, cabinets and other equipment.
2nd The doors shall be designed as to avoid the presence of surfaces that do not allow cleaning;
sliding doors shall not be used.
Article 404. The lining shall be sealed so as to prevent contamination arising from the spaces above
it.
Article 405. The piping, ducts and other utilities shall be installed in such way that these do not
create gaps difficult to clean.
Article 406. Sinks and drains shall be avoided whenever possible and such items shall not exist in
A/B areas where aseptic operations are being carried out.
1st When sinks and drains are required to be installed, such items shall be designed, located and
maintained in order to minimize the microbial contamination risks, they shall have efficient, easycleaning siphons, and suitable to avoid air and liquid backflow.
2nd The ground channels, if present, shall be open, easy-cleaning and connected to external drains,
in order to avoid introduction of microbial contaminants.
Article 407. The cleaned areas locker-rooms shall be designed to closed pre-chambers shape and
they shall be used in such way to allow the separation of different clothing change stages, thus
minimizing the microbial contamination from particles coming from protective clothing.
1st Dress rooms shall be effectively blown with filtered air.
2nd The use of segregated entry and exit locker-rooms to/from cleaned areas can be necessary in
certain occasions.
3rd The facilities intended to hand cleaning shall be located only inside the locker-rooms, never in
places where aseptic operations are carried out.
Article 408. The two pre-chamber doors cannot be open at the same time, and there shall be a
system that hinders this event.
Sole Paragraph. A sound/visual alarm system that warns for the indicated situation shall be in place.
Article 409. The cleaned areas shall have a ventilation system that insufflates the filtered air and
that maintains a positive pressure of area in relation to surrounding zones.
1st The ventilation shall be efficient and suitable to required conditions.
2nd The adjacent rooms of different grades shall have a differential pressure of approximately 1015 Pascal (reference value).

3rd Special attention shall be given to major risk zones, where the filtered air gets into contact with
the cleaned products and components.
4th It might be necessary to modify the several recommendations relative to air supply and
pressure differentials if containment of pathogenic, highly toxic, radioactive materials or materials
with live viruses or bacteria is needed.
5th In some processes, it might be necessary the using of facilities intended to decontamination
and treatment of air that is exiting the cleaned area.
Article 410. It shall be shown that the air system does not constitute contamination risk.
Sole Paragraph. It shall be ensured that such system does not allow the spreading of particles
originated from people, equipment or operations, for the major risk production zones.
Article 411. An alarm system shall be installed to indicate the occurrence of failures on the
ventilation system.
1st In addition, a pressure differential indicator shall be installed between the areas where such
difference is important.
2nd Pressure differences shall be regularly recorded.
Article 412. The unnecessary access of materials and people to critical areas shall be avoided.
Sole Paragraph. When necessary, the access shall be performed through physical barriers.
Item V
Equipment
Article 413. Conveyor belts interconnecting grade A or B cleaned areas to areas that presents lower
air classification grade shall not be used, unless the conveyor belt itself is continuously sterilized
(for example: a sterilizing tunnel). .
Article 414. When possible, the equipment used in sterile products production shall be selected in
order to make possible to sterilize them by vapor, dry heat or other method.
Article 415. When possible, the arrangement of the equipment and utilities shall be designed and
installed in order to maintenance and repair operations can be done from outside of cleaned areas.
Sole Paragraph. Equipment that have to be removed for maintenance shall be sterilized again after
reassembly, whenever possible.
Article 416. When the equipment maintenance is performed inside the cleaned areas,
cleaned/disinfected instruments and tools shall be also used.

Sole Paragraph. If the required cleanliness standards and/or asepsis of areas are not maintained
during the maintenance service, the areas shall be clean and disinfected in order to the production
be resumed.
Article 417. All equipment, including sterilizers, air filtration systems and water production systems
shall be subject to a periodic maintenance, validation and monitoring plan.
Sole Paragraph. Approval for use of equipments after the maintenance service shall be documented.
Article 418. Water treatment and distribution facilities shall be designed, built and maintained in
order to ensure a reliable suitable quality water production.
1st The system shall not be operated beyond its installed capacity.
2nd It shall be considered a forecast of the water systems monitoring and maintenance program.
3rd Water for injectables shall be produced, stored and distributed so as to prevent the growth of
microorganisms.
Item VI
Finalization of the Manufacture Stages
Article 419. The containers shall be welded using suitable and proper validated procedures.
1st Samples shall be controlled in relation to its integrity, according to the established procedures.
2nd In case of vacuum sealed containers, the samples shall be controlled to check the vacuum
maintenance according to the predetermined period of time.
Article 420. The final containers that contain parental products shall be individually inspected.
1st If it is a visual inspection, it shall be performed under suitable, controlled light and contrast
conditions.
2nd The operators intended for this job shall be subjected to periodic visual accuracy
examinations, considering corrective lenses, if applicable, and they shall have frequent resting
intervals during his/her work hours.
3rd If other methods of inspection are used, the process shall be validated and the equipment's
performance shall be verified periodically. The results shall be recorded. Results shall be logged.
Item VII
Insulators Technology
Article 421. The use of insulator technology to minimize the human interventions in the production
areas can result in a significant decrease of microbiological contamination risk arising from
environment in aseptically prepared products.

Sole Paragraph. In order to achieve this goal, the insulator shall be drawn, designed and setup so
that the air inside of it has the quality required for the process.
Article 422. The insertion and removal of materials in and out of the insulator are a couple of the
main sources of contamination. Therefore, there shall be procedures for these operations to be
carried out.
Article 423. The air classification required to insulator surrounding environment depends on its
drawing and application.
Sole Paragraph. The surrounding environment shall be controlled and for aseptic processes, at least,
a D level classification shall exist.
Article 424. Insulators shall be used only after validation. The validation shall take into
consideration all critical factors of insulators technology, such as the internal and external quality of
the insulator, sanitization, material transfer process and insulator integrity.
Article 425. The monitoring shall be routinely performed and it shall include leakage tests of
insulator and sleeves/couplings.
Item VIII
Blow/Fill/Seal Technology
Article 426. The blow/fill/seal units are equipment designed to form containers/recipients during an
ongoing operation from thermoplastic granules, then fill and seal.
1st Blowing/bottling/sealing equipments used in aseptic operations, and equipped with a level A
air blowing system, may be setup in an environment of at least C level , provided A/B level outfits
are worn.
2nd The environment shall comply with the limits of feasible and non-feasible particles.
3rd The blow/fill/seal equipment used in terminally sterilized products shall be installed in at least
a D level environment.
Article 427. The following requirements shall be complied with:
I - drawing and qualification of equipment;
II - validation and reproducibility of local cleaning and local sterilizing;

III - cleanliness classification of the area where the equipment is installed;


IV - training and outfit for the operators; and

V - interventions at equipment critical zones, including any aseptic mounting prior the bottling
start.
TITLE IV
BIOLOGICAL PRODUCTS
CHAPTER I
SCOPE
Article 428. The purpose of this Title is to complement the "Good Manufacturing Practices for
Medicinal Products", reinforcing the specific points about biologic products manufacturing.
Article 429. The regulatory procedures required for biologic products control are mostly determined
by the source of such products and by the manufacturing technologies applied.
Sole Paragraph. The manufacture procedures contained in this resolution include medications
whose active principles are obtained by means of:
I - growth of microorganism strains and of eukaryotic cells;
II - abstraction of substances from biological tissues or fluids of human, animal or vegetable origin
(allergenic solutions);

III - recombinant DNA technical (rDNA);


IV - hybridome technique; and
V - multiplication of microorganisms in embryos or in animals.
Article 430. The biological products manufactured with these technologies include allergenic
solutions, antigenes, vaccines, hormones, cytokines, enzymes, derivates of human plasma,
hyperimmune serum (heterologous), immunoglobulins (including monoclonal antibodies), products
of fermentation (including products derived from rDNA).
CHAPTER II
GENERAL CONSIDERATIONS
Article 431. The manufacturing of biologic products should be done in accordance with the basic
principles of Good Manufacturing Practices (GMP). That's why the points discussed in this Title are
considered as supplementary to the general standards established in the "Good Manufacturing
Practices for Medicinal Products" and such points are specifically related to production and quality
control of biological drugs.
Article 432. The method used to produce the biological products, as controlled and managed, make
certain special precautions necessary. Unlike conventional pharmaceutical products, which are
typically manufactured and controlled by reproducible chemical and physical techniques, the
biologic products are manufactured with technologies that involve biological material and processes
with possible of variability.

Article 433. The production process of biological substances has an intrinsic variability, and
therefore, the nature of the byproducts is not constant. For this reason, in biologic products
manufacturing the achieving of the recommendations established by GMP during all production
phases are yet more critical.
Article 434. The quality control of biologic products almost implies the employment of biological
techniques, which have a greater variability than the physical-chemical determinations. The control
during process acquires major importance in production of biologic products, since certain quality
deviations are not detected in quality control tests carried out in the finished product.
CHAPTER III
PERSONNEL
Article 435. During the work shift, the personnel should not go from areas where live animals or
microorganisms are handled to facilities where works with other products and organisms are being
performed, unless defined decontamination measures are applied, including changing of uniform
and footwear.
Article 436. The personnel designated for production should be segregated from personnel
responsible for animal care.
Article 437. All personnel directly and indirectly involved in production, maintenance, control and
animal facilities should be immunized with specific vaccines and, when necessary, subjected to
periodic exams for detection of infectious-contagious diseases traces.
Article 438. When BCG vaccines are manufactured, the access to production areas should be
restricted to personnel carefully monitored by periodic medical examinations.
Article 439. In case of blood or human plasma derivatives, the personnel should be immunized with
hepatitis B vaccine.
CHAPTER IV
FACILITIES AND EQUIPMENT
Article 440. The airborne dissemination of pathogenic microorganisms handled in production
should be avoided.
Article 441. The areas used for processing animal tissues microorganisms not used in the
production process, as well as those meant to run tests with animals or microorganisms, shall be
separated from the facilities used for the production of sterile biological products, with independent
airing systems and distinct staff.
Article 442. In the areas used for the manufacture of products in shifts, the design and layout of the
facilities and equipments shall allow effective cleaning and sanitation after production, and
whenever necessary, decontamination by means of sterilizing and/or fumes. All processes used
should be validated.

Article 443. The live microorganisms should be handled in equipment and with procedures that
ensure the maintenance of cultures purity, as well as protect the operator against contamination with
the mentioned microorganism.
Article 444. Biological products, such as vaccines with dead microorganisms, toxoids, bacteria
extracts, including those prepared through recombinant DNA technique, once inactivated, can be
bottled/filled in the same facilities used for other sterile products, since the suitable post-filling
decontamination measures, including cleanliness and sterilization, are taken.
Article 445. Biologic products originated from sporulated microorganisms should be handled in
facilities dedicated for this product group, until the inactivation process is finished.
1st When the facilities or a cluster of facilities are used to prepare sporulated microorganisms, only
a single product shall be prepared at a time.
2nd When the product uses Bacillus anthracis, Clostridium botulinum or Clostridium tetani,
segregated facilities shall be used in all stages, dedicated exclusively to each these products.
Article 446. The steps up to the viral inactivation of human plasma or blood derivative products
manufacturing should be carried out in facilities and equipment exclusively intended for this
purpose.
1st After the viral inactivation, once inactivated, such products can be filled/bottled in the same
facilities used for other sterile products, since the proper post-filling decontamination measures,
including cleanliness and sterilization, are taken.
2nd All used processes should be validated and the risk should be assessed.
Article 447. Cross contamination shall be prevented by the adoption of the following measures, if
applicable:
I - perform production and filling in segregated areas;

II - preventing the manufacture of different products at the same time, unless they are in physically
segregated areas;

III

- transferring biological materials in safety;

IV - change the clothing when entering in different production areas;


V - cleaning and decontaminating the equipments carefully;

VI - take precautions against contamination risks caused by air recirculation in clean environment
or by accidental return of the eliminated air;

VII - used "enclosed systems" in production;

VIII - take precautions to prevent aerosols formation (mainly by centrifugation and mixings);

IX - forbid entry of pathologic specimen samples not used in production processes inside areas
used
for biological substances production;

- use sterilized containers and, when appropriate, containers with documented low microbial
load.
Article 448. The preparation of sterile products should be performed in cleaned area, with positive
air pressure.
Sole Paragraph. All organisms considered as pathogenic should be handled with negative air
pressure, in locations specially reserved for this purpose, according to insulation norms for the
concerned product.
Article 449. The areas in which pathogen microorganisms are handled should have an exclusive air
circulation system and such air should not be recirculated.
1st The air should be eliminated through sterilizing filters, whose operation and efficiency should
be periodically checked.
2nd The used filters should be incinerated after disposal.
Article 450. Whenever pathogenic microorganisms pare used in production, there shall be specific
systems for decontamination of effluents.
Article 451. The piping, valves, and ventilation filters of equipment should be designed in such way
to facilitate its cleaning and sterilization.
CHAPTER V
FACILITIES FOR ANIMALS
Article 452. Animals employed in the production and quality control should be accommodated in
facilities and segregated from the other company areas, with independent ventilation systems.
Article 453. The design of facilities and the construction material used shall permit the maintenance
of areas in sanitary conditions and it also should have protection against entry of insects and other
animals.
Article 454. Personnel who works with animals should wear area-exclusive clothing.
Article 455. The animal care facilities should include isolation area for quarantine of new joined
animals and a food storage appropriate area.
Article 456. There shall be suitable facilities for animal inoculation.

Sole Paragraph. This activity shall be carried out in an area separated from those where there are
dead animals.
Article 457. A facility for cages disinfection should be in place and if possible, with steam
sterilization.
Article 458. It is necessary to control and record the health status of the animals used.
Article 459. Special precautions are required when monkeys are used in production or in quality
control.
Article 460. Packaging, storage, transportation, treatment and final deposition of residue generated
by the animals, including wastes and corpses, shall be carried out in a safe manner and comply with
the specific regulations.
TITLE V
VALIDATION
CHAPTER I
INTRODUCTION
Article 461. Validation is an essential part of the Good Manufacture Practices (GMP), and an
element of Quality Assurance associated to a product or process in particular.
1st The basic principles of quality assurance have as objective the production of products suitable
for the intended use. These principles are:
I - Quality, safety and efficiency shall be designed and established for the product;
II - Quality cannot be inspected or tested in the product; and
III - Each critical step of manufacturing process should be validated. Other process steps should be
under control in order to such products are consistently produced and meet all defined specifications
and quality requirements.
2nd Validation of processes and systems is fundamental to achieve the objectives. It is through the
validation project that a manufacturer can confidentially establish that the manufactured products
will consistently meet its specifications.
3rd Documentation related to the validation shall include:
I - Standard Operating Procedures (SOP);

II specifications;
III Master Plan of Validation (MPV);

IV - qualification protocols and reports; and


V validation protocols and reports.
CHAPTER II
RELATIONSHIP BETWEEN VALIDATION AND QUALIFICATION
Article 462. Validation and qualification are essentially components of same concept.
1st The term qualification is normally used for equipment, utilities and systems, whereas
validation is applied to processes.
2nd Qualification is part of validation.
CHAPTER III
VALIDATION
Item I
Approaches for
Validation
Article 463. There are two basic approaches for validation - one based on evidence obtained
through tests (concurrent and prospective validation), and other based on historical data analysis
(retrospective validation).
1st Whenever possible, the prospective validation is preferable.
2nd The retrospective validation is more encouraged and it is not applicable to sterile products
manufacturing. Article 464 - The concurrent validation and prospective validation may include:

I - comprehensive product test, which can involve comprehensive sampling (with estimative of
reliability limits for individual results) and demonstration of intra and inter lots homogeinety.

II - simulation of the process conditions;


III - Challenge/worst case tests, which determine the process robustness; and
IV - control of process parameters monitored during the normal production runs to obtain
additional information on process reliability.
Item II

Scope of Validation
Article 465. A sufficient and appropriated effective system should be in place, including
organizational structure, documentation, sufficient personnel and financial resources in order to
achieving the validation in the predicted deadline.
Sole Paragraph. Management and people responsible for Quality Assurance shall be involved.
Article 466. The persons in charge of executing the validation shall have suitable experience and
qualification and represent different departments depending on the validation job to be carried out.
Article 467. A specific program for validation activities also should be in place.
Article 468. The validation should be carried out in a structured manner, according to documented
procedures and protocols.
Article 469. The validation shall be carried out:
I - for facilities, equipments, utilities (e.g. water , air, compressed air, steam), systems, processes
and procedures;

III

- in periodic intervals; and

III - whenever significant changes are introduced.


Sole
Paragraph.
Periodic
re-qualifications
or
revalidations may be replaced whenever appropriate, by periodic assessment of the data and
information.
Article 470. The validation should be done according to the written
protocols. Sole Paragraph. At the end, a validation report should be
elaborated.
Article 471. The validation shall be conducted during a period of time, for example, until at least
three consecutive batches are assessed (industrial scale) in order to demonstrate the process's
efficiency. "Worst case" situations should be considered.
Article 472. There should exist a clear distinction between in-process control and validation.
Sole Paragraph. Process control encompasses tests carried out during production of each batch, in
accordance with specifications and methods established during the development phase, with the
purpose of monitoring the process continuously.
Article 473. When a new formula or manufacturing method is employed, measures to demonstrate
its suitability to the routine process should be taken.

Sole Paragraph. The defined process, using specified material and equipment, should to result in
consistent yield of a required quality product.
Article 474. The manufacturers should identify what is needed to validate in order to prove that the
critical aspects and their operations are under control.
1st Significant changes on facilities, equipment, systems and processes that could affect the
product quality should be validated.
2nd A risk assessment should be used to determine the scope and extension of the validation.
CHAPTER IV
QUALIFICATION
Article 475. The qualification should be completed before validation is conducted.
Sole Paragraph. The qualification process should constitute itself a logical and systematic process,
and it should initiated by design phase of facilities, equipment and utilities as well.
Article 476. Depending on function and operation of the equipment, utility or system, in certain
situations, only installation qualification (IQ) and operation qualification (OQ) are considered
necessary, as well as the correct operation of equipment, utilities or systems can be considered a
sufficient indicator of their performance (PQ).
Sole Paragraph. Equipment, utilities and systems should be periodically monitored and calibrated,
besides being subjected to preventive maintenance.
Article 477. The main equipment, as well as critical utilities and systems, need installation (IQ),
operation (OQ) and performance (PQ) qualifications.
CHAPTER V
CALIBRATION AND VERIFICATION
Article 478. The calibration and verification of equipment, instruments and other apparatuses, used
in production and quality control, should be performed in a regular basis.
Article 479. The personnel responsible for calibration and preventive maintenance should have
proper training and qualification.
Article 480. A calibration program should be available and it should provide information such as
calibration standards and limits, responsible persons, calibration intervals, records and actions to be
taken when problems are identified.
Article 481. The standards used for calibration should be traceable to Brazilian Calibration
Network.

Article 482. Equipment, instruments and other calibrated equipment should be labeled, coded or by
any means identified in order to indicate the calibration status and the date of the next recalibration.
Article 483. Whenever the equipment, the instrument or another device is not used for a period of
time, its operating and calibration status will be verified before usage, aiming at demonstrating
satisfactoriness.
CHAPTER VI
MASTER PLAN OF VALIDATION
Article 484. The MPV should comprise the key elements of validation program. It should be
concise and clear, as well as comprising, at least:
I - a policy of validation;
II - organizational structure of the validation activities;

III - Summary/List of facilities, systems, equipment and processes that are currently validated and
those of are still to be validated (current situation and scheduling);

IV - document templates (ex: protocol and report templates) or reference thereto;


V - planning and schedule;
VI control of changes; and
VII - references to other existing documents.
CHAPTER VII
PROTOCOLS OF QUALIFICATION AND VALIDATION
Article 485. Qualification and validation protocols that describes the studies to be conducted should
be in place.
Article 486. Such protocols shall at least include the following information:
I - objectives of the survey;
II - local/plant where the survey will take place;
III responsibilities;

IV - description of the procedures to be followed;


V - equipment to be used, standards and criteria for relevant products and processes;

VI - type of validation;
VII - process and/or parameters;
VIII - sampling, tests and monitoring requirements; and
IX - acceptance criteria.
Article 487. There shall be a description of how the results of the qualification and validation
surveys ought to be analyzed.
Article 488. The protocol should be approved before the start of the validation itself. Any changes
on protocol should be approved before being adopted.
CHAPTER VIII
QUALIFICATION AND VALIDATION
REPORTS
Article 489. Reports on accomplished qualifications and validations shall be elaborated.
Article 490. Reports shall reflect the followed protocols and contemplate, at least, the title, objective
of study, as well as referencing the protocol, details of materials, equipment, programs and cycles
used, and also the procedures and methods that were adopted.
Article 491. The results should be evaluated, analyzed and contemplated with the acceptance
criteria previously established.
1st The results shall comply with the acceptance criteria.
2nd Deviations and out-of-specification results should be investigated by the company.
3rd If such deviations were accepted, they should be justified.
4th When necessary, additional studies shall be conducted.
Article 492. The Departments responsible for qualification and validation works shall approve the
complete report.
Article 493. The report conclusion should clearly express if the qualification and/or validation was
considered successful.
Article 494. Quality Assurance shall approve the report after the final review. The criteria for
approval shall comply with the company's Quality Assurance system.

Article 495. Any deviations found during the validation process should be investigated and
documented. Corrective actions may be applicable.
CHAPTER IX
QUALIFICATION
STEPS
Article 496. There are four qualification stages:
I - project qualification (QP);
II - facility qualification (QI);

III - operation qualification (QO); and


IV - performance qualification (QD).
Article 497. All procedures for operation, maintenance and calibration should be elaborated during
the qualification.
Article 498. Training of operators should be performed and the records should be kept.
Item I
Project Qualification
Article 499. Design qualification will provide documented evidences that the design specifications
were complied with, in accordance with the user's requirements and the Good Manufacturing
Practices.
Item II
Facility
Qualification
Article 500. The facility qualification should provide documented evidence that the facility was
satisfactorily finished.
Article 501. The specifications of acquisition, drawings, manuals, equipment and parts list and
supplier details shall be checked during the facility qualification.
Article 502. Control and measurement instruments shall be calibrated.
Item III
Operation Qualification
Article 503. The operational qualification should provide documented evidence that the utilities,
systems or equipment and all their components are working in accordance with the operational
specifications.

Article 504. The tests should be outlined to demonstrate the satisfactory operation under normal
operating ranges, as well as within limits of its operating conditions (including worst case
situations).
Article 505. The operation controls, alarms, switches, panels and other operating components
should be tested.
Article 506. The measures performed with a statistical approach should be thoroughly described.
Item IV
Performing Qualification
Article 507. The performance qualification shall provide documented evidence that the utilities,
systems or equipment and all their components are working in accordance with the routine
operational specifications.
Article 508. The results of tests should be collected during a period of time to demonstrate
consistency.
Item V
Requalification
Article 509. Requalification shall be done according to an established time schedule.
Sole Paragraph. Requalification frequency shall be determined based on factors such as analysis of
results related to calibration, checking and maintenance.
Article 510. There shall be a periodic requalification, as well as requalification after changes (such
as changes on utilities, systems, equipment, maintenance services and displacements).
Sole Paragraph. There may be a periodic reviewing program for the equipments, which shall
provide support for assessment of the periodicity of re-qualification.
Article 511. The need to re-qualify after changes occur shall be considered by the change
management procedure.
Item VI
Revalidation
Article 512. Processes and procedures shall be submitted to revalidation to make sure they are still
able to lead to the expected results.
Article 513. The need of revalidation after changes shall be considered by the procedure of changes
control.
Article 514. Requalification shall be done according to an established time schedule.

Article 515. The frequency and extension of the periodic revalidation will be determined based on
risk assessment, as well as by the review of historical data (periodic review program).
Item VII
Periodic Revalidation
Article 516. Periodic revalidations shall be conducted in order to verify changes on process that
may gradually occur throughout a period of time, or by wear of equipment.
Article 517. When a periodic revalidation is conducted, the following documents shall be
considered:
I Master formula and specifications;
II - operating procedures;

III - registries (e.g., calibration, maintenance and cleaning records); and


IV - analytical methods.
Item VIII
Revalidation after Changes
Article 518. The revalidation after change(s) should be conducted when such change could affect
the process, procedure, quality of product and/or characteristics of product.
Sole Paragraph. Revalidation shall be considered as part of change control procedure.
Article 519. The extension of the revalidation depends on the nature and significance of change(s).
Article 520. The changes should not adversely affect the product quality or process characteristics.
Article 521. The changes that require revalidation shall be defined in the validation plan and may
include:

I - change of input materials (including physical properties like density, viscosity or distributions
of particles size, which affect the process or product);

II - change of raw material manufacturer;


III - transference of process to other plant (including facility changes that affect the process);
IV - changes of primary packaging material (i.e.: substitution from plastic to glass);
V - changes on manufacturing process (i.e.: mixing times , drying temperatures);

VI - equipment changes (e.g. addition of automatic detection systems, installation of new


equipment,
major revisions of machinery or apparatuses and damages);

VII - changes on production area and support systems (i.e.: rearrangement of areas, new water
treatment method);
VIII - negative quality arising trends;
IX - arising of new discoveries based on current knowledge (i.e.: new technologies); and
X - changes in support systems;
Sole Paragraph. Changes of equipment involving replacement of equipment with a equivalent one
that normally does not require revalidation. For example, a centrifugal pump that is replacing an
older model does not necessarily require revalidation.
CHAPTER X
CONTROL OF CHANGES
Article 522. The company should establish a change management system aiming to keep under
control the changes that are likely to produce an impact over qualified systems and equipment, as
well as about already validated processes and procedures, that whether could affect or not the
quality of manufactured products.
Article 523. The procedure should describe the actions to be adopted, including the necessity and
extension of the qualification or validation to be achieved.
Article 524. The changes should be formally requested, documented and approved before
implementation. The records should be kept. Records shall be logged.
CHAPTER XI
PERSONNEL
Article 525. Suitable personnel qualification shall be demonstrated, when relevant.
Article 526. The personnel that requires qualification includes, for example:
I - laboratory analysts;
II - personnel responsible for execution of critical procedures;

III - personnel in charge of entering data into the computer systems; and
IV - risk assessment staff.

TITLE VI
WATER FOR PHARMACEUTICAL USE
CHAPTER I
GENERAL REQUIREMENTS FOR WATER SYSTEMS FOR PHARMACEUTICAL USE
Article 527. The production, storage and distribution systems for pharmaceutical water should be
planned, installed, validated and maintained in order to ensure the production of suitable quality
water.
1st The system shall not be operated beyond its planned capacity.
2nd The water shall be produced, stored and distributed in such way that to avoid microbiological,
chemical or physical contamination.
Article 528. Any unplanned maintenance or change shall be approved by Quality Assurance.
Article 529. The sources of water and treated water shall be monitored regularly as to the chemical
and microbiological quality.
1st The performance of purification, storage and distribution systems should be monitored.
2nd Records of monitoring results and actions taken shall be maintained by a determined period of
time.
Article 530. The water treatment degree shall consider the nature and intended use of intermediate
or finished product, as well as the production process step in which the water is used.
Article 531. When chemical sanitation of the water systems is part of the biocontamination control
program, a procedure shall exist to make sure the sanitizing agent is effectively removed.
CHAPTER II
WATER QUALITY SPECIFICATIONS
Item I
Potable Water
Article 532. The potable/drinking water should be supplied under continuous positive pressure in a
piping system free from any defects that could lead to contamination of any product.
Article 533. Tests shall be carried out periodically to confirm that the water complies with the
standards required for potable water.
Item II
Purified Water

Article 534. The purified water shall comply with the specifications of the pharmacopoeias accepted
by ANVISA.
Article 535. The water purification system should be designed in such way to avoid microbiological
contamination and proliferation.
Item III
Water for Injectables
Article 536. The water for injectables shall comply with the specifications of the pharmacopoeias
accepted by ANVISA.
Article 537. Water for injectables shall be used in the preparation of sterile products.
Sole Paragraph. The water for injection shall be used in the final flushing after cleaning of
equipment and components that gets into contact with sterile products.
Article 538. Vapor, when it gets into contact with a sterile product in its final container or in
equipments designed for sterile products preparation, should comply with the specifications of
water for injection, when such vapor condensates.
CHAPTER III
METHODS FOR WATER
PURIFICATION
Item I
General Considerations
Article 539. The method selected for water purification, or purification steps sequence, shall be
suitable for the concerned application.
Sole Paragraph. The following items should be considered when selecting the water treatment
method:
I - the water quality specification;
II - performance or efficiency of the purification system;

III - quality of the water for feeding and seasonal changes; and
IV - reliability and robustness of water treatment equipment that is running.
Article 540. The specifications for water purification equipment, storage and distribution systems
should take into consideration the following items:
I - risk of contamination from lixivia of contact materials;

II - adverse impact of absorbable contact materials;

III - project that allows sanitization of system, when required;


IV - resistance against corrosion;
V - free from leakages;
VI - configuration to avoid microbiological proliferation;
VII - tolerance to cleaning and sanitization agents (thermal and/or chemical);
VIII - the system capacity and production demand requirements; and
IX
- installation of all instruments, sampling points necessary to allow monitoring the critical
parameters of system.
Article 541. The project, configuration and layout of water purification equipment and storage and
distribution systems should also consider the following variable physical considerations:
I - room available for installation;
II - structural loads on buildings;

III - possibility of proper access for maintenance; and


IV - the ability to handling regeneration and chemical sanitization chemical products in a safe
manner.
Item II
Production of Potable Water
Article 542. The quality of potable water should be routinely monitored.
1 Further tests shall be conducted if there is any change on raw water source, changes on
treatment techniques and on system configuration.
2 If the potable water quality significantly changes, the direct use of such water in
pharmaceutical processes or as supply water for later treatment steps shall be reviewed and the
result of such review shall be documented.
Article 543. In cases which the potable water is derived from a system proper for raw water
treatment, the water treatment steps used and system configuration should be documented.
Sole Paragraph. Changes in the system or in its operation shall not be carried out until the relevant
review is completes and the change is approved by Quality Assurance.

Article 544. If the potable water is stored and distributed, the storage system should allow the
maintenance of water quality before its use.
1st After any storage, tests should be conducted according to a defined methodology.
2nd When water is stored, its use shall be subject to sufficient renewal to prevent stagnation.
Article 545. The equipment and systems used to produce potable water should allow draining and
sanitization.
Sole Paragraph. The storage tanks should be closed with properly protected air vents and should
allow visual inspection, draining and sanitization.
Item III
Production of Purified Water
Article 546. The following items should be considered when configuring a water purification
system:
I - the supply water quality and its seasonal variation;
I - the water quality specification;

III - the required sequence of purification steps;


IV - the required pre-treatment extension to protect the final purification steps;
V - performance optimization, including yield and efficiency of treatment unit;
VI - suitable location of the sampling points, so as to prevent contamination; and
VII - adoption of instruments to measure some system parameters, for example: flow, pressure,
temperature, conductivity, pH and overall organic carbon.
Article 547. Periodic assessment of potential microbiological contaminations of sand filters,
multimedia filters, activated charcoal beds and softeners shall be carried out, in the case they are
present.
1st Measures should be taken for contamination control, such as backwashing, chemical or thermal
sanitization and frequent regeneration, in order to avoid the system contamination and biofilm
formation.
2nd The possibility of all the water treatment components being kept in continuous flow in order
to inhibit the growth of microorganisms shall be taken into consideration.

Article 548. Microbiological and sanitation control mechanisms shall be adopted for the purified
water systems, maintained in ambient temperature, once these are particularly subject to
microbiological contamination, above all when the equipments are static during periods of little or
no demand for water.
Item IV
Production of Water for Injectables
Article 549. The following items should be considered for planning a injection water production
system:
I - the quality of feeding water;
I - the required water quality specification;
III - optimization of the water generator size, in order to prevent frequent system startups/halts; and
IV - the discharge and emptying functions.
CHAPTER IV
WATER PURIFICATION, STORAGE AND DISTRIBUTION SYSTEMS
Item I
General
Article 550. The storage and distribution system should be arranged in order to prevent water
recontamination and it should be subjected to a combination of online and offline monitoring to
ensure that the appropriate water specification is maintained.
Item II
Materials that Get in Contact with Systems that Distribute Water for Pharmaceutical Use
Article 551. The materials that come into contact with water for pharmaceutical use, including
piping, valves and frames, seals, diaphragms and instruments, should be selected to achieve the
following objectives:
I - compatibility: all materials used shall be compatible with the temperature and chemical
substances used by the system or that are inside it;
II - Leakage prevention: all material that gets into contact with the water for pharmaceutical use
should not have leaks within the working temperature range;

III - resistance against corrosion: purified water and water for injectables are highly corrosive. To
prevent system failure and contamination of water, the selected materials should be suitable, the
welding process should be carefully controlled and all seals and components should be suitable to
the piping used. The system should be subjected to passivation after first installation or after
modification. When passivation is performed, the system should be entirely cleaned before use, and

the passivation process should be carried out in alignment with a clearly established documented
procedure.

IV - smooth inner finishing: Smooth inner surfaces shall be used for they help avoid coarseness
and racking in the system of water for pharmaceutical use;
V - welding: The selected system materials should be able to be easily jointed by weld in a
controlled manner.

VI design of flanges or joints: whenever flanges or unions are used, they should be of hygienic or
sanitary design. Checkings to ensure that the correct sealings are used and also to ensure that they
are correctly fitted and adjusted should be performed.

VII

- documentation: all system components shall be entirely documented; and

VIII - materials: Suitable materials that may be considered sanitary elements of the system shall be
used.
Item III
System Sanitation and Control of Microbiological Load
Article 552. Water treatment equipment, storage and distribution systems used for purified water
and water for injection should be provided with features to prevent microbiological contamination
during normal use, as well as techniques for sanitizing or sterilizing the system after intervention for
maintenance or modification.
Sole Paragraph. The sanitation or sterilizing techniques employed shall be considered during
design planning of the system and its performance shall be evidenced during the qualification
activities.
Article 553. Systems that operate and are maintained at elevated temperatures, in the range of 7080C, are generally less susceptible to microbiological contamination than systems that are
maintained at lower temperatures.
Sole Paragraph. When lower temperatures are required due to water treatment process employed or
the temperature requirements for the water in use, then special precautions should be taken to
prevent the ingress and proliferation of microbiological contaminants.
Item IV
Storage Capacity of Containers
Article 554. The capacity of storage vessel should be determined on the basis of the following
requirements:

1 it is necessary to provide a buffer capacity between the generation rate of the water treatment
equipment and the consumption on the different user points;

II - the equipment for water treatment shall work continuously for significant periods of time in
order to prevent inefficiency and wear-off, which occurs when the equipment is turned on and off
too often; and
III - the capacity should be sufficient to provide short-term reserve in the event of failure of the
water
treatment equipment or inability to produce water due to a sanitization or regeneration cycle.
Item V
Contamination Control of Storage Containers
Article 555. The following should be taken into account for the efficient control of contamination:
I - the headspace in the storage vessel is an area of risk where water droplets and air can come into
contact at temperatures that encourage the proliferation of microbiological organisms;
II - the reservoirs shall be configured to prevent dead zones where there may be microbiological
contamination;

III - vent filters are fitted to storage vessels to allow the internal level of liquid to fluctuate. The
filters should retain bacteria, hydrophobic and ideally be configured to allow on-site integrity
testing. Offline tests are also acceptable; and

IV - where pressure-relief valves and bursting discs are used on storage vessels to protect them
from over-pressurization, these devices should be of sanitary design.
Item VI
Requirements for the Water Distribution Piping System
Article 556. Distribution of purified water and of water for injectables shall be carried out
preferably using a continuous circulation ring.
Sole Paragraph. Proliferation of contaminants within the storage tank and distribution loop should
be controlled.
Article 557. Filtering shall not be used in the distribution rings or in outlets to control
biocontamination. Such filters are likely to conceal system contamination.
Article 558. Where heat exchangers are employed to heat or cool pharmaceutical water within a
system, precautions should be taken to prevent the heating or cooling utility from contaminating the
water.
Article 559. Circulation pumps should be of sanitary design that prevents contamination of the
system.

Article 560. The use of biocontamination control techniques shall be considered isolatedly or
jointly, in order to prevent the use of water out of the specifications established.
CHAPTER V
OPERATIONAL CONSIDERATIONS
Item I - Qualification
Article 561. All water systems for pharmaceutical use are considered critical systems for quality
and of direct impact, therefore they shall be qualified.
Article 562. The process of qualification shall comply with procedures written and approved in
advance. The data obtained shall be duly recorded and reviewed for approval.
Article 563. During the process of qualification, potential seasonal variations that might affect the
quality of the water for pharmaceutical use shall be considered.
Item II
Continuous Monitoring of the System
Article 564. After completion of the water system qualification, a review of the data obtained,
corrective actions adopted and adequacy of the operating procedures, if necessary, shall be carried
out. After the review, a routine monitoring plan shall be deployed.
Article 565. That monitoring shall comprise a combination of online monitoring of process
parameters, as well as offline tests to verify compliance with the chemical and microbiological
specifications.
1st The offline samples should be taken from points of use and specific sample points.
2nd Samples of usage points shall be collected in a similar way to that adopted when the water is
being used in service.
Article 566. Tests to ensure the accomplishment of the pharmacopoeia specification should be
carried out.
Article 567. The monitoring data should be subject to trend analysis.
CHAPTER VI
WATER SYSTEMS
MAINTENANCE
Article 568. A maintenance program for the water system that comprises the following items should
be established:
I - defined frequency for system equipment and instruments;
II - calibration program;

III - procedures for specific tasks;


IV - control of parts to be used;
V - time schedule and maintenance instructions;
VI - log, revision and approval of the executed service(s); and
VII - log and review of problems and fails during maintenance.
CHAPTER VII
SYSTEM REVIEW
Article 569. The water systems (purified water and water for injection) shall be reviewed and in
suitable regular intervals.
1 s t The review team shall include representatives from engineering, quality assurance, operations
and maintenance areas.
2nd The revision shall consider topics such as:
I - changes made since the last review;
II - system performance;
III reliability;

IV - quality trends;
V flaws;
VI - investigations;
VII - out-of-specification results obtained during the
monitoring;
VIII- setup changes;
IX - updating of installation documentation;
X log books; and
XI - situation of the current list of operating procedures.

TITLE VII
COMPUTER INFORMATION SYSTEMS
Article 570. The introduction of a computer information system in the production chain, including
storage, distribution and quality control does not exempt the necessity to accomplish other items of
standard.
1st Whenever computer systems replace operating manuals, there shall be no impacts in the product
quality.
2nd It shall be considered the risk of losing the quality aspects of the previous system due to
reduction of operators involvement.
Article 571. Collaboration among the key personnel and the persons who are responsible for the
computer system should exist.
1st People who occupies responsibility positions shall receive training for managing and
utilization of the systems which are under their responsibility.
2nd It shall be ensured that people having the needed knowledge are available to assist in project
aspects, development, validation and operation of the computer system.
Article 572. The validation extension depends on a series of factors, including the intended use of
the system, the type of validation to be carried out (concurrent and prospective) and the insertion of
new elements.
Article 573. Validation shall be considered part of the computer system's life cycle, which includes
the planning, specification, scheduling, test, documentation, operation, monitoring, maintenance
and change stages.
Article 574. Computer systems shall be installed in locations where external factors do not interfere
in its operation.
Article 575. There shall be a detailed documentation of the system, always maintained up to date.
The description may include system diagrams and technological infrastructure (hardware, software
etc.).
Sole Paragraph. The user of the computer system shall ensure that all software building steps were
performed in accordance with quality assurance system.
Article 576. The software is a critical component of the computer system. The user of the computer
system shall ensure that all software building steps were performed in accordance with quality
assurance system.
Article 577. The system shall include, when applicable, the verification of the data input and its
processing.

Article 578. Before starting to use a computer system, system's capacity to store the desired data
shall be tested and confirmed, guaranteeing the necessary technological infrastructure for full
operation.
Sole Paragraph. When a replacement of a manual system with a computer system occurs, both
systems shall run in parallel as part of testing and validation.
Article 579. The data inputs and modifications may only be performed by authorized personnel.
1st Measures shall be adopted that do not allow unauthorized persons to add, delete or modify data
in the system, whereas security measures may be used, such as passwords, personal codes, access
profiles, keys or restricted access to the system's workstations.
2nd It shall be established a defined access management procedure such as issue, change and
cancel the passwords of people who are no longer authorized to log on, input and change data in the
system, including change of user password.
3rd Systems which enable registering attempts from unauthorized people to accessing are
preferable
Article 580. Whenever critical data is inserted manually (for example: weighed value, heavy input
batch number) there shall be an additional verification to assure accuracy of the inserted data.
Sole Paragraph. Such verification can be performed by a second operator or through validated
electronic means.
Article 581. System shall register the identification of operators which input or confirm critical data.
The authorization for data changing shall be restrict.
1st Any critical data changing shall be documented, describing the reason for such change(s)
2nd When data is modified, logs of all entries, changes, users and dates shall be maintained.
Article 582. Changes in systems or programs shall be carried out in accordance with the system
development procedures and methodologies.
1st The procedures shall define the validation, verification, approval and implementation of the
changes.
2nd Any change shall only be recorded and implemented with the approval of the person in charge
of the part of the system involved.
3rd Any significant changes shall be validated.
Article 583. In the events of quality audits, it should be possible to obtain hard copies of the
electronically stored data.

Article 584. Data shall be stored in a secure manner, in physical or electronic means, protected
against accidental or intentional damages.
1st Stored data shall be checked for accessibility, durability and accuracy.
2nd If modifications on equipment or programs are proposed, the above mentioned verifications
shall be carried out in an appropriate frequency for the storage medium in use
Article 585. Data shall be protected by means of backup copies made at regular intervals.
1st Backup data shall be stored for a defined period of time, and in a safe and separate location.
2nd There shall be procedures to make sure the data backup retrieving and maintenance process is
duly carried out.
3rd Lost data shall be treated as a deviation.
Article 586. There shall be alternatives for running systems in case of incidents in operation.
1st The time needed to implement the use of these alternatives shall be related to a potential
urgency of necessity to use them.
2nd For example, information required to perform a collection shall be available in a short time
space.
Article 587. Procedures to be complied with in case of failure or shutdown of the system's operation
shall be defined and validated.
Sole Paragraph. Any failures and corrective measures taken shall be recorded.
Article 588. It should be established procedures to record and analyze the system errors and
allowing that corrective measures are adopted.
Article 589. In case of outsourcing computer systems development and maintenance services, there
shall be a formal agreement executed, including the contractor's responsibilities.
Article 590. When the delivery of batches for sale is accomplished by using a computer system, the
system shall recognize that only the designated persons are allowed to release the batches and also it
shall log the responsible for this operation.
TITLE VIII
GOOD MANUFACTURING PRACTICES OF PHITOTHERAPICS
Article 591. This Title completes the Good Manufacturing Practices for Medicinal Products, in
view of the necessity to a specific addressing of the Phytotherapic Products.

Sole Paragraph. This Topic exclusively provides for phytotherapic medications and does not
comprise the combination of vegetable origin materials with those of animal or mineral origins,
isolated active substances, among others.
CHAPTER I
GENERAL CONSIDERATIONS
Article 592. Due to the inherent complexity of medicinal plants, the production and processing have
direct influence on THE quality of phytotherapic medications.
Sole Paragraph. The application of Good Manufacturing Practices for Phytotherapics is an essential
tool to ensure the quality of a product.
CHAPTER II
QUALITY
CONTROL
Article 593. In addition to the use of suitable analytical techniques to characterize the phytotherapic
medications, the warranty of quality also requires control of the vegetable raw materials as well
validation of the analytical process and methodologies.
Sole Paragraph. An appropriate quality assurance (QA) system shall be applied in manufacturing of
phytotherapic medications.
CHAPTER III
SANITATION AND HYGIENE
Article 594. Due to its origin, the vegetal materials may contain microbiological contaminants.
Sole Paragraph. In order to prevent changes and reduce any type of contamination, it is necessary to
apply to suitable level of sanitation and hygiene in all stages of the manufacturing process.
CHAPTER IV
VALIDATION
Article 595. The company shall exhibit technical justification for determining the tests to be
conducted during the cleanliness and process validation.
CHAPTER V
SELF-INSPECTION
Article 596. At least one member of the self-inspection team shall have the experience and /or
technical qualification in the area of phytotherapic medications.
CHAPTER VI
PERSONNEL

Article 597. The delivery of phytotherapic medications to market shall be authorized by the person
who has technical experience and qualification on the specific aspects of processing and quality
control of phytotherapic medications.
CHAPTER VII
TRAINING
Article 598. All personnel involved in manufacturing shall have suitable and periodic training in
Good Manufacture Practices and in areas of specific knowledge, phytotherapic medications and
medicinal plants.
CHAPTER VIII
PERSONAL HYGIENE
Article 599. All personnel involved in manufacturing shall be trained in Good Personal Hygiene
Practices, as well as being protected against the contact with potentially allergenic vegetable raw
materials, by wearing the suitable individual protection outfit and equipment.
CHAPTER IX EQUIPMENT
Article 600. Equipment shall be sterilized by means of specific cleaning procedures suitable to the
process and duly validated, in order to prevent contamination.
CHAPTER X SAMPLES AND
REFERENCE STANDARDS
Item I
Reference Standards for Identification of Vegetable Drugs
Article 601. Upon non-existence of an essay containing the description of the vegetable drug in
pharmacopoeias acknowledged by ANVISA, the technical identification report issued by a qualified
professional, or a description in a technical-scientific indexed publication and a chromatographic
profile or phytochemical prospection may be used as references.
Item II
Reference Standard for Active Raw Materials and Phytotherapic Medicament Quality
Control
Article 602. The Reference standard may be a substance defined chemically (for example, a wellknown active component or a marker substance or a class of chemical compounds present in the
vegetable raw materials) or a standard abstract.
1st Reference standards officially approved by the Brazilian Pharmacopoeia or other codes
authorized by the legislation in force, or else duly characterized reference standards.
2nd Reference standard shall have the quality fit for this purpose.

3rd All reference standards shall be stored in proper conditions to avoid degradation.
4th For characterized reference standards, the full technical report of assessment shall be
submitted, including nuclear magnetic resonance, mass spectrometry (high resolution), infrared,
melting point and/or HPLC (pureness based in the peak-related area).
5th The standard abstract shall be mentioned in relation to a primary standard, in order to evidence
its identity and the marker's content.
CHAPTER XI DOCUMENTS
Item I Specifications
Article 603. The specifications for vegetal raw material and phytotherapic medications are aimed to
define the quality and ensure the safety and efficiency. Such specifications shall include, at least, the
following information, when applicable:
I vegetable raw material:

a) Official botanic nomenclature;


b) part of the plant used;
c) tests for identification of known active principles or markers. A standard sample should be made
available for identification purposes;

d) description based on visual(macroscopic) and/or microscopic examination;


e) tests of pureness and integrity, including: total ashes and/or insoluble ashes in chloridric acid,
humidity, drying loss, foreign matters and heavy metals researches.
f) tests to determine microbiological contamination, pesticide residue and fumes, radioactivity and
mycotoxines, if applicable;

g) other relevant tests, including residual solvents used to abstract the derivate; and
h) qualitative and quantitative analyses on the active principles and/or markers when known, or
classes of chemical compounds typical of the species.
II - phytotherapic medications:

a) tests to determine microbiological contamination;


b) weight uniformity, disintegration time, hardness and friability, viscosity, consistence and
dissolution time, if applicable;

c) physical appearance such as, color, odor, form, size and texture;

d) loss for drying or water content;


e) tests for identification, qualitative determination of relevant substances of the plants (for
example, fingerprint chromatograms);

f) quantification of markers, and analytical methods available; and


g) limit tests for residual solvents.
Article 604. The vegetable raw materials derivates that contain genetically modified organisms shall
comply with the specific standards in force.
Article 605. The Quality Control tests and specifications for phytotherapic medications shall
contemplate the qualitative and quantitative determination of the main active components.
1st If the therapeutic activity of the constituents is known, this information shall be included in the
documentation.
2nd In cases where therapeutic activities of the constituents cannot be quantitatively determined,
the specifications shall be based on the determination of markers.
3rd In both cases, specification of content shall be defined.
Article 606. Whenever the Phytotherapic Medicament has associations of vegetable species where
the quantitative determination of a marker per species is not possible, the chromatographic profile
contemplating the presence of at least one typical substance of each species of the medicament may
be submitted, complemented by the dose-ranging of at least one marker, provided it is duly
justified.
CHAPTER XII
QUALITY CONTROL
Article 607. All the Quality Control staff shall have the knowledge, experience, technical
qualification and be trained to carry out analyses on vegetable drugs, vegetable drug derivates and
phytotherapic medications.
TITLE IX
FINAL AND TRANSITIONAL PROVISIONS
Article 608.
A term of one year is hereby granted for preparation of all the protocols and other documents
necessary for the validation of the computer systems that are already setup, whereas the conclusion
of the validation surveys shall occur within a limit term of 3 (three) years, as of the date of
publication of this resolution.
Sole Paragraph. For systems acquired as of the date of publication of this resolution, the validation
shall be carried out before their use in the routine they are meant to.

Article 609. The Steering Committee shall publish updates of this resolution, with the purpose of
monitoring the development of new technologies of the pharmaceutical industry.
Article 610. Non-compliance with the provisions of the present resolution configures sanitary tort,
as provided by Act No. 6437, of August 20, 1977, whereas the offender shall be subject to the
penalties provided in this legal instrument.
Article 611. It is revoked the Ordinance SVS/MS nbr. 500 of October 9, 1997 and Resolution RDC
nbr 210, of August 4, 2003.

Article 612. This resolution takes force on the publication

date.

DIRCEU BRS APARECIDO BARBANO

ANNEX

Table 1 Limits for microbiological contamination


Levels

Air Samples
(UFC/m)

A
B
C
D

<1
10
100
200

Sedimentation Plates
(diameter of 90mm)
(UFC/4 hours)
<1
5
50
100

Contact Plates
(diameter of 55mm)
(UFC/plate)
<1
5
25
50

Gloves Contact
Test (5 fingers)
(UFC/glove)
<1
5
-

Individual sedimentation plates may be exposed for less than 4 hours.

Table 2 Air classification system for the production of sterile products.

LevelAt restIn operation


Maximum number permitted of particles/m3Maximum number permitted of
particles/m3
> 0,5 um> 5,0 um> 0,5 um> 5,0 umA3
520203.52020B3.52029352.0002.900C352.0002.9003.520.00029.000D3.520.0
0029.000Not definedNot defined

Table 3 Comparison between the different classification systems for clean areas, at rest.
OMS - GMPUnited StatesABNT NBR ISO 14644-1EC - GMP(Usual)Level AClass 100ISO
4,8*Level ALevel BClass 100ISO 5Level BLevel CClass 10.000ISO 7Level CLevel DClass
100.000ISO 8Level D

* Source: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary
Use, Annex 1 - Manufacture of Sterile Medicinal Products. Review: November, 2008.