National Sanitary Surveillance Agency www.anvisa.gov.br

Resolution - RDC No. 210, August 4, 2003 D.O.U. [Federal Gazette] from August 14, 2003

The Collegiate Directory of the National Sanitary Surveillance Agency, within its attributions, granted to it by the art. 11, subparagraph IV, of the ANVISA Regulation, approved by the Decree No. 3.029, from April 16, 1999, according to the art. 111, subparagraph I, item ‘b’, paragraph 1 of the Internal Rule approved by the Guideline No. 593, from August 25, 2000, republished on December 22, 2000, in a meeting called on July 30, 2003,

whereas Act No. 6.360, from September 23, 1976; whereas Decree No. 79.094, from January 5, 1977; whereas Act No. 9.782, from January 26, 1999; whereas the need of updating the Good Manufacturing Practices of Drugs, with the

purpose of following the development of new technologies, in the last years, and the significance of national and international documents on the issue;

whereas the World Health Organization (WHO) recommendations, on the Quality

Certification of Pharmaceuticals, international marketing object; whereas the need to standardize the actions of Sanitary Surveillance; adopts the following Collegiate Directory Resolution and I, CEO, determine its publication: Art. 1 To determine to all manufacturing sites of drugs, the fulfillment of the guidelines

established in the Technical Regulation of Good Manufacturing Practice of Drugs, according to Annex I of this Resolution.

Art. 2 To institute and approve the Classification and Evaluation Criteria of the items in

the Inspection Guide for Drug Manufacturing Companies, based on potential risk of quality and safety, inner to the drug manufacturing processes, according to Annex II of this Resolution.

Art. 3 To institute as an inspection rule to the purpose of verifying the fulfillment of the

Good Manufacturing Practice of Drugs, to the sanitary surveillance authorities of the Single Health System [Sistema Único de Saúde], the Inspection Guide for Drug Manufacturing Companies, according to Annex III of this Resolution.

Art. 4 The drug manufacturing companies must perform self-inspections, according to the

Technical Regulation of the Good Manufacturing Practice of Drugs and the Inspection Guide in Pharmaceutical Industry, foreseen in this Resolution, as part of the measures required to their implementation.

Ministry of Health

Single paragraph. The reports of self-inspection, related to this article, must be available, to be handled and/or sent promptly to the fiscal authorities, whenever formally required by them.

Art. 5 The Resolution - RDC No. 134, from July 13, 2001, is revoked. Art. 6 The Annexes A, B, I and L of Decree - No. 500, from October 9, 1997, are revoked. Art. 7 The updates of this Resolution, viewing the follow-up of the development of new

technologies, in the pharmaceutical sector, must be approved by the Collegiate Directory of the National Sanitary Surveillance Agency, and published in the Federal Gazette.

Art. 8 The non-conformity or disobedience to what is provided in this Resolution, figures a

sanitary misdemeanor, in the Act No. 6437, from August 20, 1977, subjecting the infractor to the penalties foreseen in this legal diploma.

Art. 9 This Resolution is valid from the date of its publication.

CLÁUDIO MAIEROVITCH PESSANHA HENRIQUES

ANNEX I

TECHNICAL REGULATION OF GOOD MANUFACTURING PRACTICES TO THE

PRODUCTION OF DRUGS Table of Contents

A. GENERAL CONSIDERATIONS 1. Glossary B. FIRST PART: Quality Management on the Manufacturing of Drugs: philosophy and fundamental elements.

1. Quality Assurance

2. Good Manufacturing Practices for Drugs (GMP)

3. Quality Control

4. Sanitization and Hygiene

5. Validation

6. Complaints

7. Products Withdrawal

8. Manufacturing and/or Analysis Agreement

9. Self-Inspection and Quality Audit

9.1 Self-inspection team

9.2 Frequency of the self-inspection

9.3 Report of self-inspection

9.4 Follow-up actions

9.5 Quality audit

9.6 Suppliers audit

10. Personnel

10.1 Generalities

10.2 Main Personnel

10.3 Training

10.4 Health, Hygiene, Garments and Conduct

11. Premises

11.1 Generalities

11.2 Auxiliary areas

11.3 Storage areas

11.4 Weighing area

11.5 Production area

11.6 Quality control area

12. Equipment

13. Materials

13.1 Generalities

13.2 Raw-material

13.3 Packaging material

13.4 Intermediary product and bulk products

13.5 Finished products

13.6 Reproved and returned materials and products

13.7 Withdrawn products

13.8 Returned products

13.9 Reagents and mean of culture

13.10 Reference standards

13.11 Waste materials

13.12 Diverse materials

14. Documentation

14.1 General aspects

14.2 Labels

14.3 Quality control essay specifications and procedures

14.4 Specifications to raw material and packaging material

14.5 Specifications to intermediary products and bulk products

14.6 Specifications to finished products

14.7 Master formula / Standard formula

14.8 Packaging instructions

14.9 Records of production batches

14.10 Packaging records of the batches

14.11 Standard Operation Procedures - SOPs and their records

B. SECOND PART: Good Manufacturing and Quality Control Practices

15. Good Manufacturing Practices

15.1 General aspects

15.2 Prevention of cross-contamination and bacterial contamination in the manufacturing

15.3 Production operations: intermediary and bulk products

15.4 Packaging operations

16. Good Quality Control Practices

16.1 Raw material, intermediary, bulk and finished products control

16.2 Required essays

16.3 In-process control

16.4 Finished products

16.5 Revision of the production records

16.6 Stability study

C. THIRD PART: Supplementary Guidelines

17. Sterile Products

17.1 General aspects

17.2 Sterile products manufacturing

17.3 Final sterilization products

17.4 Products sterilized by filtration

17.5 Sterile products prepared from sterile raw materials, in aseptic conditions

17.6 Personnel

17.7 Facilities

17.8 Equipment

17.9 Sanitization

17.10 Production

17.11 Sterilization

17.12 Sterilization by heat

17.13 Sterilization by humid heat

17.14 Sterilization by dry heat

17.15 Sterilization by radiation

17.16 Sterilization by ethylene oxide

17.17 Filtration of drugs which may not be sterilized in their final containers

17.18 Finalization of the manufacturing steps

17.19 Quality control

18. Biological Products

18.1 Reach

18.2 Glossary

18.3 General Considerations

18.4 Personnel

18.5 Premises and Equipment

18.6 Production

18.7 Labeling

18.8 Batch records

18.9 Quality Assurance

18.10 Quality Control

18.11 Premises to animals

19. Validation of the Manufacturing Processes

19.1 Reach

19.2 Glossary

19.3 General considerations

19.4 Types of process validation

19.5 Pre-requisites to the validation of a production process

19.6 Approaches

19.7 Organization

19.8 Scope of a process validation program

19.9 Master Validation Plan A. GENERAL CONSIDERATIONS Registered drugs must only be produced by licensed manufacturers, holding the Manufacturing Authorization, with their activities regularly inspected by the National Sanitary Authorities in charge. This Regulation of Good Manufacturing Practices (GMP), must be used as reference in the inspection of the manufacturing site premises, the manufacturing and quality control processes and as a training material of the drugs sector inspectors, as well as, in the training of the professionals responsible for the production and Quality Control in industries. GMP are applicable to all operations involved in the manufacturing of drugs, including those drugs in development designed to clinical essays. The Good Manufacturing Practices (GMP) described in this document are passive of continuous updates, in order to follow the evolution of new technologies. Alternative actions may be adapted in a way to meet specific needs of certain product, provided that they are validated to ensure the product quality. GMPs do not cover aspects related to the safety of the personnel involved in the manufacturing process; these aspects are regulated by a specific legislation. However, the manufacturer must ensure the safety of its workers. This document is divided within three parts:

B. First Part: “Quality Management on the Manufacturing of Drugs: philosophy and fundamental elements” briefs the general concepts of Quality Assurance, as well as the main components and subsystems of GMP, determines the responsibilities of the superior management team, of the production management and of the Quality Control, including, but not restricted to, hygiene, validation, personnel, premises, equipment, materials and documentation. C. Second Part: “Good Manufacturing and Quality Control Processes”, which acts as a guide of the actions to be taken separately by the people responsible for the production and the Quality control in the implementation of the general principles of Quality Assurance. D. Third Part: It contains the supplementary guidelines to the manufacturing of sterile drugs, biological products and validation, but it is not a finished section, because it foresees the inclusion of other matters, such as the ones related to phytotherapeuticals and pharmaceutical active ingredients (PAIs). 1. Glossary The definitions presented below apply to the terms used in this Regulation. They may have different meanings in other contexts. Adjustment Operation designed to make a measuring instrument have a performance compatible to its use. Area Delimited physical space, where the operations are performed under specific environmental conditions. Clean area Area with environmental control related to the contamination by viable and non-viable particles, designed, constructed and used in a way to decrease the introduction, generation and detention of contaminants in its inner part. Antechamber Closed space with two or more doors, placed between two or more areas of distinct cleanliness classes, with the purpose of controlling the air flow between them, when they need to be entered. The antechamber is designed in a way to be used by people or materials. Reference sample Raw materials and finished products samples kept by the manufacturer, duly identified, for a determined period of time after the finished product expiration date. The amount of sample must have, at least, the double of the units required to perform all the analyses foreseen in official compendia. Representative sample Amount of sample statistically calculated, representing the sampled universe, taken for purposes of the analysis to the batch release. Certification Verification, upon sanitary inspection, of the whole fulfillment of the Good Manufacturing Practices in some working production lines, pharmaceutically. Calibration Set of operations establishing, under specific conditions, the relation among the values shown by an instrument or measuring system or values represented by a materialized measure or a reference material, and the correspondent values of the greatness established by patterns. Certificate of product registration Legal document issued by the Sanitary Authority in charge, where the qualitative and quantitative formula of the product, including details on the package, label and expiration date, are shown. Certificate of Good Manufacturing Practices Legal document issued by the Sanitary Authority in charge, certifying that a certain production line of the company meets the requirements of the Good Manufacturing Practices. Concentration Quantity of active(s) or inactive(s) substance(s) in a determined mass or volume unit of the product. Cross-contamination

Contamination of certain raw material, intermediary product, bulk product or finished product by another raw material, intermediary product, bulk product of finished product, during the production process. In-process control Verifications performed during the production, in order to manage and, if necessary, to adjust the process to ensure that the product is according to its specifications. The environmental or equipment control may also be considered an integrating part of the process control. Component Any substance or material to be used in the manufacturing of a pharmaceutical product. Quality deviation Distancing of the established quality parameters for a product or process. Edification Set of architectural premises containing the areas, premises and auxiliary resources. Packaging All the operations, including filling and labeling, which the bulk product must go through in order to become a finished product. Usually, the sterile filling is not considered as a part of the packaging product, even though the bulk product is kept in the primary container. Specification Document describing, in details, the requisites that the products or material used or obtained must meet during the manufacturing. The specifications act as the basis for the quality evaluation. Manufacturing All the operations including the acquirement of materials, production, quality control, release, storage, issuing of finished products and the related controls. Manufacturer Holder of the Authorization of Establishment to the manufacturing of drugs, issued by the authority in charge of the Ministry of Health, according to the provided in the current sanitary legislation. Master formula/Standard formula Document or set of documents specifying the raw materials and package materials with their quantities, together with the description of the procedures and necessary precautions to the production of a certain amount of finished product. Besides, it provides instructions on the processing, including the in-process controls. Installation Delimited physical space containing machinery, apparatus, equipment and auxiliary systems used to perform the processes. Batch Defined quantity of raw material, packaging material or finished product manufactured in only one process or process series, which fundamental characteristic is the homogeneity and quality within the specified limits. In the continuous manufacturing, the batch corresponds to a definite fraction of the production. Sometimes it is necessary to divide the batch into sub-batches, which will later be mixed in order to form a final homogeneous batch. Raw material Any active or inactive substance, with defined specification, used in the production of drugs. Packaging material Any material, used in the packaging process of a certain pharmaceutical product. Drug Pharmaceutical product, technically obtained or elaborated, with a prophylactic, healing, palliative or diagnosis purposes Batch number Defined combination of numbers and/or letters identifying a certain batch. Production order Reference document to the production of a drug batch, comprehending the information of the master formula/standard formula. Authorized Person

Licensed professional in the area of drugs, indicated by the company, responsible for the release of the batches of finished products to their distribution and selling. Strength Therapeutic activity of the pharmaceutical product according to the shown by lab essays, or by clinical data properly developed and controlled. Expiration Date Limited date to the use of a pharmaceutical product defined by the manufacturer, based on its respective tests of stability, the storage conditions kept and transportations established by it. Standard Operation Procedure (SOP) Written and authorized procedures providing detailed instructions to the performance of specific operations in the manufacturing of a pharmaceutical product and other general nature activities. Process Set of procedures to the performance of a determined operation, following the techniques, rules, and specifications. Production All the operations involved in the preparation of a determined pharmaceutical product, since receiving the materials from the warehouse, passing by processing and packaging, until the obtainment of the finished product. Bulk product Any product that went through all the production steps, not including the packaging process. The injectables in their primary package are considered a bulk product. Returned product Finished product, marketed and issued, returned to the manufacturer. Intermediary product Product partially processed, which must go through the subsequent production steps. Finished product A product that went through all the production steps, including labeling and final packaging. Medical Control Program of Occupational Health: With the purpose of promoting and preserving the health of all the workers. It is an inner part of the broader group of initiatives of the company in the workers health field. It shall consider the incidental questions about the individual and the group of workers, giving place to the clinical-epidemiological instrumental in the approach of the relation between your health and your work. It shall have a prevention, tracking and early diagnosis character of the damages to health related to work, including the ones of sub-clinical nature, besides of noticing the existence of cases of professional disease or irreversible damages to the workers’ health. Qualification Operations documented according to a pre-determined tests plan and defined acceptance criteria, ensuring that components, equipment and premises are appropriate to the intended use. Quarantine Temporary detention of raw material, packaging material, intermediary products, bulk or finished products, while awaiting the release decision, rejection or reprocessing. Reanalysis Analysis performed in a raw material, previously analyzed and approved, in order to confirm the maintenance of the specifications established by the manufacturer, within its expiration date. Reconciliation Procedure with the purpose of comparing the actual production quantity and the established theoretical quantity in the different production steps of a product batch. Recovery Total or partial incorporation of previous batches, of proven quality, to other batch, in a defined production step. Batch record

Set of documents related to the manufacturing of a determined batch of finished product. These documents describe the production procedures and record all the operations related to the batch quality. Reprocessing Rework of all or part of a batch of the product out of one or more established quality parameters, from a defined production step, so its quality may become acceptable through one or more additional operations. The reprocessing must be previously authorized and performed according to approved procedures. System Regulated standard of activities and interactive techniques gathered to form an organized set. Great Volume Parenteral Solutions (GVPS) Aqueous, sterile, apyrogenic solutions, filled into a single container of 100 ml or more, with final sterilization. In this definition are included the solutions to intravenous administration, solutions for irrigation and solutions for peritoneal dialyses. Active substance Any substance presenting a pharmacological activity or other direct effect on the diagnosis, healing, relieve, treatment or prevention of diseases, or which affects the human body functioning. Validation Documented act attesting that any procedure, process, equipment, material, operation or system really leads to the expected results. B. FIRST PART: Quality Management on the Manufacturing of Drugs: philosophy and essential elements. The quality management is the aspect of the management function which determines and implements the “Quality Policy”, i.e., the global intentions and directions related to quality, formally expressed and authorized by the superior management team of the company. The basic elements of the quality management are: - appropriate infrastructure or “quality system”, comprehending organizational structure, procedures, processes and resources; - systematic and accurate actions in order to ensure that a certain product (or service) meets the requirements as for its quality. The set of these actions is called “Quality Assurance”. Within an organization, the Quality Assurance acts as a management tool. In situations provided in agreements, the Quality Assurance acts, also, to provide truth in the supplier. In the manufacturing and supply of drugs, the term “Quality Assurance” comprehends elements such as the organization structure, processes and procedures. The concepts of Quality Assurance, GMP and Quality Control are inter-related aspects of quality management. They are written in this Regulation in order to emphasize their relations and essential significance to the manufacturing of drugs. 1. Quality Assurance 1.1 “Quality Assurance” is the whole set of actions taken with the purpose of ensuring that the drugs are within the quality standards requires, so they can be used for due purpose. Therefore, Quality Assurance comprehends GMPs and other factors, including the design and development of a product, which are not covered by the purposes of this Regulation. 1.2 An appropriate Quality Assurance system, applied to the manufacturing of drugs, must ensure that: (a) the drugs as designed and developed taking into consideration the need of fulfilling the GMP and other requests such as Good Laboratory Practices (GLP) and Good Clinical Practices (GCP); (b) the operations of production and control are clearly specified, in written, and the GMP requirements are met; (c) the management responsibilities are clearly specified in the description of titles and functions;

(d) actions are taken as for the manufacturing, supply and correct use of raw materials and package materials; (e) all the controls are performed in the raw materials, intermediary products, bulk products, as well as other in-process controls, calibrations and validations; (f) the finished product is correctly processed and checked, according to defined procedures; (g) the drugs are not issued before authorized persons have certified that each production batch was produced and controlled according to the requests of the record and other applicable regulations related to the production, control and release of pharmaceutical products; (h) instructions are provided and the necessary actions are taken in order to ensure that the drugs are stored by the manufacturer, distributed, and subsequently, handled, so their quality is maintained during all period before expiration date; (i) there is a self-inspection and/or internal audit procedures of the quality, evaluating, regularly, the effectiveness and the application of the Quality Assurance system. 1.3 The manufacturer is responsible for the quality of the drugs it manufactures, ensuring that they are appropriate to the purpose they are intended for, meet the requirements established in their records and do not place the patients’ at risk for presenting inappropriate safety, quality or efficacy. Meeting this purpose is the responsibility of the superior management team of the company and it required the participation and commitment of employees in the many departments and in all organization, supplying companies and distributors levels. In order the achieve the quality purpose trustfully, there must be a Quality Assurance system totally structured and correctly implemented, incorporating the GMPs. This system must be totally documented and must have its effectiveness monitored. All the parts of the Quality Assurance system must be constituted by competent and licensed personnel, besides having enough and appropriate space, equipment and premises. 2. Good Manufacturing Practices for Drugs (GMP) 2.1 Good Manufacturing Practice is the part of the Quality Assurance ensuring that the products are consistently produced and controlled, with quality standards appropriate to the intended use, requested by the registration. The fulfillment of GMP is firstly oriented to decrease the inherent risks to any pharmaceutical production, which cannot be detected through essays in the finished products. The risks are essentially constituted by: cross-contamination, particles contamination and exchange or mixing of products. 2.2 The GMPs determine that: (a) all the manufacturing processes must be clearly defined and systematically revised in relation to the experience obtained. Besides, they must be able to manufacture drugs, within the quality standards required, meeting the respective specifications; (b) the critical steps of the manufacturing processes and any significant change must be systematically validated; (c) the production areas must be provided with all the infrastructure required, including: qualified and duly trained personnel; appropriate space and premises; appropriate equipment and services; appropriate materials, containers and labels; approved procedures and instructions; appropriate storage and transportation; premises, equipment and qualified personnel, to the in-process control; (d) the instructions and procedures must be written in a clearly, unambiguous language and must be specifically applicable to the premises used; (e) operators must be trained to perform the procedures correctly; (f) records must be done (manually and/or through recording instruments) during the production, in order to show that all the steps contained in the procedures and instructions were followed and that the quantity and quality of the product obtained are according to the expected. Any significant deviation must be recorded and investigated;

(g) the records related to the manufacturing and distribution, making the complete tracking of a batch possible, must be kept organized and easy to access; (h) the appropriate storage and distribution of products must minimize any risk to its quality; (i) a system able to collect any batch, after its sale or supply, must be implemented; (j) the complaints on marketed products must be examined, registered and the quality deviation causes must be investigated and documented. Measures must be taken in relation to the products presenting quality deviations and actions must be adopted in order to prevent reoccurrences. 3. Quality Control 3.1 Quality control is a part of GMP related to the sampling, specifications, essays, organization procedures, documentation and release procedures ensuring that the necessary and significant essays are performed and that materials are not released to use, nor to sales or supply, until their quality is considered satisfactory. The quality control must not be limited to the laboratory operations, it must also be involved in all decisions related to the product quality. 3.2 All the holders of Authorization of Establishment to manufacture drugs must have a Quality Control. It is essential that the quality control is independent of the production. The quality control must be independent from the other departments and it must be under the direction of a qualified and experienced person, with one or many control laboratories available. Appropriate resources must be available in order to guarantee that all of the quality control activities are effective and trustfully performed. The minimum requirements to the quality control are the following: (a) appropriate premises and personnel, trained personnel and operation procedures approved must be available so the sampling, inspection and essays of raw materials, packaging materials, bulk products and finished products may be performed, whenever necessary, to manage the environmental conditions of the areas; (b) the sampling of raw materials, packaging materials, intermediary products, bulk products and finished products, must be performed through approved methods and by qualified personnel; (c) the analysis methods must be validated; (d) the records must be done (manually and/or through recording instruments), showing that all the sampling procedures, inspections and essays required, are really performed and that any deviation is totally investigated and documented; (e) the finished products must have inputs, meeting the quantitative and qualitative composition described in the product registration; the substances must present the required purity, must be packaged into appropriate containers, correctly labeled. (f) the results obtained in the inspections and the materials, intermediary products, bulk products or finished products control essays for meeting the specifications, must be recorded. The products batches evaluation must include the revision and evaluations of the production documentation, as well as, the evaluation of the deviations to specific procedures; (g) no product batch may be released to expedition before being approved by the authorized person, who must indicate that it is according to its specifications; (h) sufficient samples of the raw materials and the finished products must be taken, in order to perform later product examinations, if necessary; the samples of finished product taken must be kept in their final packages, in the established storage conditions, unless they are exceptionally large; 3.3 The quality control has, yet, other attributions, such as establishing, validating and implementing its procedures to evaluate, keep and store the reference standards of the active substances used; ensuring the proper labeling of the material and product containers; ensuring that the active substances and the products stability is monitored; taking part in the investigation of the complaints related to the product quality and taking part in the environmental management. All these operations must be performed according to the approved, and whenever required, registered Standard Operation Procedures (SOP).

3.4 The evaluation of the finished products must comprehend all the significant factors, including the production conditions, the results of the in-process control, the manufacturing documents, the meeting of the finished product specifications and the examination of the final package. 3.5 The company Quality Control personnel must have access to the production areas in order to perform the sampling and investigation activities, as appropriate. 4. Sanitization and Hygiene 4.1 The production of drugs requires a high sanitization and hygiene levels, that must be kept in all manufacturing procedures. The sanitization and hygiene activities must comprehend personnel, premises, equipment and apparatus, production materials and containers, cleaning and disinfectant products and any other aspect which may constitute a contamination source to the product. The potential contamination sources must be eliminated through a broad sanitization and hygiene program. 5. Validation 5.1 The validation studies constitute an essential part of the GMP and, therefore, they must be conducted according to predefined protocols. A written report must be kept with the summary of the results obtained and the conclusions. The processes and procedures must be established, according to the validation study results and they must be periodically revalidated, so to ensure that they are able of reaching the planned results. Special attention must be given to the validation of processes, control essays and cleaning procedures. 5.2 The processes considered critical must be validated, concurrently, prospectively and/or retrospectively. 5.3 When there is a change in the master formula/standard formula or a new preparation method is introduced to the usual manufacturing processes, the appropriateness of the new method to the established routine processes must be shown by validation. The process defined upon the use of the specified materials and equipment, must show to be able of originating uniform products, within the required quality standards. 5.4 The manufacturing processes suffering any significant change, including any equipment or materials change which may affect the quality and/or reproducibility of the process, must also be validated. 6. Complaints 6.1 All the complaints and other information related to products with possible quality deviations, must be carefully investigated and registered according to the written procedures. 6.2 A person responsible for the receiving of complaints and for the actions to be taken must be indicated. This person must have enough support personnel to help him/her in this function. If the person indicated is not the Technician Responsible for the product, he/she must be informed. 6.3 In case of complaints of possible quality deviation of a product, the written procedures describing the actions to be taken, including the need to perform a likely collection, must be adopted. 6.4 Any complaint related to a quality deviation in a certain product must be registered, together with all the details in the batch records and, then, it must be completely investigated. The person responsible for the Quality Control must be involved in the study of the related deviation. 6.5 If a quality deviation is detected in some product batch, or if there is a likely suspicion of deviation of a certain batch, the possibility that other batches present the same problem it must be taken into account, therefore, they must also be verified. Other batches containing the reprocessed product of the batch presenting deviations, must be specially investigated. 6.6 Whenever required, the appropriate actions of follow-up must be adopted after the investigation and evaluation of the complaint, including the possibility of collecting the product.

6.7 All the decisions and measures taken as a result of certain complaint must be registered and mentioned in the correspondent batch records. 6.8 The complaint records must be regularly revised, with the purpose of detecting any mark of specific or recurrent problems, which require more attention and may justify the collection of the marketed products. 6.9 The sanitary authorities in charge must be informed by the manufacturer when any significant quality deviation in the manufacturing process, product deterioration is detected, and when a serious problem with the quality of some product is under investigation. 7. Products Collection 7.1 There must be a system for the immediate and efficient withdrawal of products presenting quality deviations or under suspicion from the market. 7.2 A person responsible for the measures to be adopted and the coordination of the product collection from the market must be indicated. This person must have enough support personnel in order to help him/her in all of the aspects of the collection and with the necessary urgency level. Usually, this person must not belong to the selling and marketing authority, and if he/she is not the Technician Responsible for the product, the latter must be informed of any action taken. 7.3 There must be written procedures, regularly verified and updated, to proceed with any collection activity. The collection operations of the product in the market must be immediate, starting, most preferably, by hospitals and drugstores. The procedures viewing the destination of the collected products, which were deviated from the transportation and/or distribution chains must be foreseen. 7.4 All of the sanitary authorities in charge in the countries the product was sent to must be immediately informed about any intent collection of the product presenting a quality deviation or under suspicion. 7.5 The records about the batch distribution presenting a quality deviation or under suspicion must be immediately available to the person responsible for the collection. The records must have enough information on the distributors and on the buyers who may have been directly supplied with the product, including in case of exported products information on the buyers who received samples to perform clinical trials and medical samples, so the product is efficiently withdrawn from the market. 7.6 The collection process progress must be recorded, including the reconciliation between the distributed quantities and the collected quantities of the product, as well as a final report. 7.7 The efficiency of the activities related to the recollection must be periodically evaluated. 7.8 An instruction indicating the storage conditions of the products withdrawn from the market, which must be kept in safety, in separated areas, while awaiting the decision about their destination, must be included. 8. Manufacturing and/or Analysis Agreement 8.1 The manufacturing and/or analysis agreement must be mutually agreed and controlled between the parties, to avoid mistakes which may result in a process, product or analysis of unsatisfactory quality. A written agreement must be signed between the contracting and the contracted parties, clearly establishing the attributions of each party. The agreement must establish the procedure upon which the authorized person must exercise its responsibilities, as for the release of each product batch for sale or as for the issuing of a certificate of analysis. 8.2 All the conditions established in the manufacturing and/or analysis agreement must include any change proposed in the technical procedures which must be in accordance with the registration of the respective product. 8.3 The written agreement signed must establish the manufacturing and/or analysis procedures of the product with all the technical activities related to both. 8.4 The agreement must establish that the contacting party may perform an audit in the contracted party premises. 8.5 In case of an analysis agreements, the final approval to the release of the finished product for marketing, must be given by the contracting party authorized Person.

8.6 The contracting party is responsible for the qualification evaluation of the contracted party to perform the contracted services. Besides, it must be assured, by the signed agreement, that the GMP principles described in this Regulation are followed. 8.7 The contracting party must provide the contracted party with all the information required to perform the contracted operations according to the product registration, as well as any other legal requirements. The contracting party must ensure that the contracted party is informed of any problem related to the product, service or essays, placing their premises, equipment, personnel, other materials or products at risk. 8.8 The contracting party must ensure that all the processed products and materials delivered by the contracted party meet their specifications or that the product has been released by the Authorized Person. 8.9 The contracted party must have appropriate premises, equipment and knowledge, besides experience and qualified personnel, in order to satisfactorily perform the service requested by the contracting party. The manufacturing contract may only be performed by manufacturers holding a Certificate of Establishment and Sanitary License. 8.10 The contracted party may not repass the services foreseen in the contract to third parties without the previous evaluation and approval by the contracting party of this agreement change. The agreements signed between the contracted party and third parties, must foresee the availability of analytical information and information on the manufacturing, just as the agreements signed between the contracting and the contracted parties. 8.11 The contracted party must abstain from performing any activity which may adversely affect the quality of the manufactured and/or analyzed product to the contracting party. 8.12 The agreement signed between the contracting and the contracted parties must specify the responsibilities of the related parties as for the manufacturing and the control of the product. Technical aspects of the agreement must be written by qualified persons, with the required knowledge in pharmaceutical technology, quality control analyses and GMP. All the actions related to the manufacturing and analysis must be according to the product registration and must be agreed by both parties. 8.13 The agreement must specify the mean by which the Authorized Person ensures that each batch is manufactured according to the Product Registration. 8.14 The agreement must clearly describe the responsibilities for the acquirement, control essay and material release, by the production and performance of the quality controls, including the in-process controls, as well as the responsibilities by the sampling and performance of the analyses. 8.15 The agreement must establish that the manufacturing records, the analytical records and the reference samples must be kept by the contracting party or must be available to it. 8.16 The agreement must establish that the distribution records must be kept by the contracting party. 8.17 The agreement must predict the actions to be adopted when there is disapproval of raw materials, intermediary products, bulk products and finished products. 9. Self-Inspection and Quality Audit The purpose of the self-inspection is to evaluate the fulfillment of GMP by the manufacturer in all of the aspects of production and the quality control. The self-inspection program must be designed in a way to detect any deficiency in the GMP implementation and to recommend the necessary corrective actions. The self-inspection must be routinely performed, in cases of product withdrawal or repeated disapprovals. The team responsible for the self-inspection must be constituted by professionals who may objectively evaluate the fulfillment of GMP. All the recommendations on the corrective actions must be implemented. The procedures to the performance of the self-inspection must be documented and also have an effective follow-up program. Written procedures must be elaborated on the self-inspection, in order to have a minimum and uniform standardization of the requirements. These procedures must comprehend, at least, the following aspects: (a) personnel; (b) premises; (c) maintenance of buildings and equipment;

(d) storage of raw material, packaging material and finished product; (e) equipment; (f) manufacturing and in-process control; (g) quality control; (h) documentation; (i) sanitization and revalidation; (j) validation and revalidation programs; (k) calibration of instruments and measuring systems; (l) collection procedures of the product from market; (m) management of complaints; (n) labels control; (o) wastes disposal; (p) results of previous self-inspections and any corrective actions adopted. 9.1 Self-inspection team 9.1.1 The Quality Assurance management must designate a team to perform the self-inspection, formed by qualified professionals and experts in their own acting areas and familiar to the GMPs. The team members may be company employees or outer experts. 9.2 Frequency of the self-inspection 9.2.1 The frequency of the self-inspections must be, at least, annual. 9.3 Self-inspection report 9.3.1 A report must be done after the self-inspection is finished, and it must contain: (a) the self-inspection results; (b) evaluations and conclusions; (c) the corrective actions recommended. 9.4 Follow-up actions 9.4.1 The Company Management and the Quality Assurance must evaluate the self-inspection, as for the corrective actions recommended, if required. 9.4.2 The verification of the fulfillment of the corrective actions, recommended in the Self-Inspection report must present a specific report. 9.5 Quality audit 9.5.1 The self-inspection complementation with quality audits may be necessary. The quality audit consists in the examination and evaluation of part or totality of a certain quality system, with the specific purpose of enhancing it. Generally, it is performed by outer, independent experts or by a team designated by the management for this purpose. Besides, the audits may be extended to suppliers and contracted parties. 9.6 Suppliers audit 9.6.1 The Quality Assurance must be responsible, together with the departments involved in the manufacturing, by the qualification of the suppliers of raw materials and packaging materials, in order to meet the established specifications. 9.6.2 Before the suppliers are approved and included in the suppliers list of the company, they must be evaluated, whenever applicable, by audits, viewing the verification of the fulfillment of GMPs. 10. Personnel 10.1 Generalities 10.1.1 The establishment and maintenance of a Quality Assurance system and the manufacturing of drugs, depend on the personnel performing them. For this reason, there must be qualified personnel enough to perform all the activities the manufacturer is responsible for. All the individual responsibilities must be established on written procedures and they must be clearly understood by all the people involved. 10.1.2 The manufacturer must have a sufficient number of qualified persons. The responsibilities attributed to each employee must not be too extensive, putting the product quality at risk. 10.1.3 The company must have an organization chart. All the employees with responsibility status must have their specific attributions written and enough authority to perform them. Their

attributions may be delegated to designees, with a satisfactory qualification level. There may not be a failure or overlapping in the personnel responsibilities as for the application of GMPs. 10.1.4 All personnel must know the GMP principles and receive initial and continuous training, including hygiene instructions as needed. All personnel must be motivated to support the company in maintaining the quality standards. 10.1.5 Actions must be taken in order to avoid the entrance of non-authorized persons in the manufacturing, storage and Quality Control areas. People not working in these areas must not use them as a shortcut. 10.2 Main Personnel 10.2.1 All professionals acting in the drugs manufacturing, occupying the main positions in the company and having the power of decision. The main personnel includes the person responsible for the manufacturing, for the Quality Assurance, for the quality control, for sales and distribution and the technical responsible. The person responsible for the production and Quality Control must be independent from each other. 10.2.2 The main positions must be occupied by people who work full time in the company. In large companies, there may be the need to delegate some functions, however, responsibilities may not be delegated. 10.2.3 The persons responsible by the departments of manufacturing, Quality Control and Assurance of drugs, must have the graduation qualifications foreseen by the current legislation and practical experience. 10.2.4 The persons responsible for the production, Quality Control and Assurance, under certain circumstances, must work together, such as: (a) authorization of procedures and documents, including their updating; (b) management and control of the manufactory environment; (c) hygiene; (d) validation of process and calibration of analytical instruments; (e) training, including the application of the quality assurance principles; (f) approval and monitoring of material suppliers; (g) approval and monitoring of the contracted manufacturers; (h) specifications and monitoring of the storage conditions of materials and products; (i) documents/ records archive; (j) monitoring of the GMP achievement; (k) inspection, investigation and sampling, in order to monitor factors that may affect the product quality. 10.2.5 The person responsible for the production, usually, holds the following responsibilities: (a) to ensure that the products are produced and stored according to the appropriate procedures, with the quality required; (b) to approve the instructions related to the manufacturing operations, including the in-process controls, and ensuring their strict implementation; (c) to ensure that the manufacturing records are evaluated and signed by a person designated, before it is made available to the quality control; (d) to verify the maintenance of the premises and equipment; (e) to ensure that the processes validations, the calibrations and control of equipment are performed and recorded and that the reports are available; (f) to ensure that the appropriate initial and continuous training is performed with the personnel in the production area, and that it is appropriate to the needs. 10.2.6 The person responsible for the Quality Control has the following responsibilities: (a) to approve or reject the raw materials, the packaging materials and the intermediary products, bulk or finished; (b) to evaluate the batches records; (c) to ensure that all the essays required are performed; (d) to approve the sampling instructions, the specifications, the essay methods and the procedures of quality control; (e) to approve and manage the analyses performed, foreseen in an agreement; (f) to verify the maintenance of the premises and equipment;

(g) to ensure that the necessary validations are done, including the validation of the analytical procedures and the calibration of the control equipment; (h) to ensure that initial and continuous trainings of the personnel of the Quality Control area are performed, according to the sector needs. 10.3 Training 10.3.1 The manufacturer, upon a written and defined program, must train the people involved in the production areas, quality control laboratories, as well as all people whose activities may interfere with the product quality. 10.3.2 Besides the theoretical and practical basic training of GMP, recently hired people must take part into the integration program and receive the appropriated training as for their attributions and they must be continuously trained and evaluated. The training programs must be made available for all personnel, as well as approved by the persons responsible for the production, quality control and Quality Assurance, keeping records. 10.3.3 Personnel working in clean areas, in areas with contamination risks, where highly active, toxic, infectious or sensitizing materials are handled, must receive a specific training. 10.3.4 The concept of Quality Assurance and all the measures which may enhance its understanding and its implementation must be broadly discussed during the training. 10.4 Health, Hygiene, Garments and Conduct 10.4.1 All the personnel must be subjected to a health evaluation before their admission and then, from time to time, required to the activities performed, according to the established procedures. 10.4.2 All personnel must be trained in the personal hygiene practices. All the people involved in the manufacturing processes must meet the hygiene rules; especially, they must be instructed to wash their hands before getting into the production areas. In order to have this rule obeyed, instructive signs must be affixed and they must be observed. 10.4.3 The people with suspicion or confirmation of an illness or exposed wound which may adversely affect the products quality, may not handle raw materials, packaging materials, intermediary products and bulk products or finished products until his/her health status does not represent a risk to the product. 10.4.4 All the employees must be instructed and motivated to report immediately to their supervisor any condition, related to the production, equipment or personnel, which they consider that may adversely interfere in the products. 10.4.5 Direct contact between the operator’s hands and the raw materials, primary packaging materials, intermediary products and bulk products must be avoided. 10.4.6 In order to ensure the product protection against contaminations, the employees must wear clean garments, appropriate to each production area. If reusable, the uniforms must be kept in closed environments, until they are washed, and when applicable, disinfected or sterilized. 10.4.7 The uniforms must be provided by the manufacturer according to written procedures. The washing of the uniforms is a company responsibility. 10.4.8 In order to ensure the employees safety, the manufacturer must have a Collective Protection Equipment (CPE) and Individual Protection Equipment (IPE) according to the activities developed. 10.4.9 It is prohibited to smoke, eat, drink, chew or keep plants, food, drinks, tobacco and personal drugs in the production areas, quality control laboratory and storage areas or any other areas where these actions may adversely affect the product quality. 10.4.10 The personal hygiene procedures, including wearing appropriate clothes, must be used by all the people entering the production areas. 10.4.11 Visitors and non-trained people, must be prohibited of entering the production areas. If this is unavoidable, these persons must be previously oriented on personal hygiene and wearing appropriate garments and they must be accompanied by a designee. 11. Premises

11.1 Generalities 11.1.1 The premises must be located, designed, built, adapted and kept properly for the operations being performed. Its design must minimize the risk of mistakes and make the cleaning and maintenance possible, in a way to avoid cross-contamination, accumulation of dust and dirt or any adverse effect that may affect the products quality. 11.1.2 The premises must have environments presenting a minimum risk of contamination of materials or products handled there when taken into consideration together with the measures designed to protect the manufacturing operations. 11.1.3 The premises used in the manufacturing of drugs must be designed and built in a way to make the appropriate cleaning possible. 11.1.4 The premises must be kept in good conservation, hygiene and cleaning status. It must be ensured that the maintenance and repairing operations do not present any risk to the products qualities. 11.1.5 The electric power, illumination, air conditioning (temperature and humidity) and ventilation supply must be appropriate, in order not to directly or indirectly affect the drugs during the manufacturing and storage processes or the appropriate functioning of equipment. 11.1.6 The premises must be designed and equipped in order to allow the maximum protection against the entrance of insects and other animals. 11.2 Auxiliary areas 11.2.1 The resting rooms and cafeteria must be apart from the other areas. 11.2.2 The locker rooms, lavatories, and restrooms must be of easy access and appropriate to the number of users. The restrooms must not have direct communication with the production and storage areas. 11.2.3 The maintenance areas must be at separated sites from the production areas. If the tools and repair parts are kept in the production area, they must be in rooms or lockers reserved to this purpose. 11.2.4 The biotherium must be isolated from the other areas, have a separate entryand an exclusive ventilation system. 11.3 Storage areas 11.3.1 The storage areas must have capacity enough to make the organized storage of a number of materials categories and products possible: raw materials; packaging materials; intermediary products, bulk products and finished products, in their quarantine, approved, reproved, returned or collected status. 11.3.2 The storage areas must be designed in a way to ensure the ideal storage conditions. They must be kept clean, dry and with temperatures compatible to the materials stored. When special storage, temperature and humidity conditions are required, they must be provided, verified, monitored and registered. 11.3.3 In the receiving and issuing areas the materials must be protected against the temperature ranges. The receiving areas must be designed and equipped to allow that the materials containers are cleaned before their storage. 11.3.4 The quarantined products must be in a restricted and separated storage area. This area must be clearly marked and their access allowed only to authorized persons. Any other system substituting the physical quarantine must offer the same safety, ensuring its release to marketing. 11.3.5 There must be a separated area to the collection of raw materials samples. If the sampling is performed in the storage area, it must be performed in a specific environment for this purpose, in order to avoid the possibility of microbiological contamination and/or cross-contamination. 11.3.6 The storage of materials or products returned, reproved or collected must be done in a separated and identified area. 11.3.7 The highly active materials, substances presenting risk of dependency, fire or explosion and other dangerous substances must be stored in secure and protected areas, duly separated and identified, according to the specific current legislation.

11.3.8 The storage of printed materials must be done safely, with restricted access, avoiding mixings and deviations, and it must be handled by a designee, following the defined and written procedures. 11.4. Weighing area 11.4.1 The areas designed to the weighing of raw materials may be located in the warehouse or in the production area, and they must be designed and separated to this purpose, with an independent and appropriate exhaustion system, avoiding cross-contamination. 11.5 Production area 11.5.1 To minimize the possibility of a cross-contamination, there must be exclusive and separated premises to the production of certain drugs, such as biological preparations (alive microorganisms), hormones and cytotoxic substances. The existence of separated buildings to highly sensitizing substances (penicillin, cephalosporin and their derivatives) is recommended. 11.5.2 The production of certain drugs, such as some antibiotics and highly active products, must not be performed in the same premises. In exceptional cases, such as damages (fire, flood, etc) or emergency situations (war, etc.), the campaign work principle in the same premises may be conducted, provided that all the specific precautions are taken and the necessary validations performed. 11.5.3 The physical premises must be disposed according to the continuous operational flow, in order to allow the production to correspond to the production operation sequences and to the required cleaning levels. 11.5.4 The production and storage areas must allow the logical and ordered positioning of the equipment and materials, in order to minimize the risk of mixings between different drugs or their components and to avoid the cross-contamination and to reduce the risk of omission or misapplication of any manufacturing or control step. 11.5.5 In the areas where the raw materials, primary package materials, intermediary products or bulk products are environmentally exposed, the inner surfaces (walls, floor and ceiling) must be covered by plain, impermeable, washable and resistant material, free of joints and cracks, easy to clean, allowing the disinfection and it must not release particles. 11.5.6 The pipes, lamps, ventilation points and other installations must be designed and installed in a way to make cleaning easy. Whenever possible, the maintenance access must be located out of the production areas. 11.5.7 The drains must be of an appropriate size, siphoned, to avoid liquids or gas reflux and they must be kept closed. Whenever possible, the installation of open drain pipes must be avoided. If required, they must be flat to make cleaning and disinfection easier. 11.5.8 The production areas must have an effective ventilation system, with air control units, including the temperature control and, whenever necessary, the humidity and filtration appropriate to the products handled there, to the operations performed and to the environment status. These areas must be regularly monitored during the production period and at rest, in order to ensure that the area specifications are met. 11.5.9 The physical premises to the drugs packaging must be designed in a way to avoid mixtures or cross-contaminations. 11.5.10 The production areas must be illuminated, according to each operation need, specially in the places where the visual control in the production line is performed. 11.6 Quality control area 11.6.1 The quality control laboratories must be separated from the production areas. The areas where the microbiological, biological or radioisotopic essays are going to be performed must be independent and separated, and they must have independent installations, specially the air system. 11.6.2 The control laboratories must be designed in a way to make the operations performed there easier. They must have space enough to avoid mixtures and cross-contaminations.

Besides, there must be enough and appropriate space to the storage of reference samples, reference standards and the documentation of the batches records. 11.6.3 The laboratory must be projected taking into account the use of appropriate building materials and it must have an air system to avoid the formation of hazardous vapors. 11.6.4 The use of separated rooms may be necessary to protect certain instruments presenting electric interference, vibrations, excessive contact with humidity and other external factors. 12. Equipment 12.1 The equipment must be designed, built, adapted, installed, located and kept in a way to make the operations to be performed there easier. The design and the location of the equipment must minimize the risks of mistakes and allow the appropriate cleaning and maintenance to avoid cross-contamination, accumulation of dust and dirt, and, usually, to avoid every effect that may have a negative influence in the products quality. 12.2 The fixed pipes designed to the conduction of fluids, must be duly identified, according to the current legislation and, when applicable, the flow direction must be indicated. When dealing with hazardous gases and liquids, connections or adaptors, not exchanged among themselves, must be used. 12.3 All the instruments used must be duly identified. 12.4 The scales and measuring instruments in the production and quality control areas must have the required capacity and accuracy and must be periodically calibrated. 12.5 The control laboratory instruments and equipment must be appropriate to the procedures and analyses foreseen and in sufficient number to the volume of operations. 12.6 The equipment used in the production must not present any risk to the products. These equipment parts in direct contact with the product must not be reactive, additive or absorptive, influencing the product quality. 12.7 The cleaning and washing processes of the equipments must not constitute a contamination source. 12.8 Every equipment out of use or presenting defects must be withdrawn from the production and quality control areas, whenever possible, or it must be duly identified. 13.1 Generalities 13.1.1 All the materials and products must be placed in quarantine immediately after they are received or produced, until they are released by the quality control, to use and distribution. 13.1.2 All the materials and products must be stored under appropriate conditions according to the procedures established by the manufacturer. The separation of batches and the stock rotation must follow the following rule: first to expire, first to leave (PEPS [FEFL]). 13.2 Raw materials 13.2.1 The acquisition of raw materials must be performed by qualified and trained employees. 13.2.2 The raw materials must only be acquired from the qualified suppliers, included in the company’s suppliers list, preferably, directly from the producer. The specifications established by the manufacturer related to the raw materials must be discussed with suppliers. All the production and quality aspects of the raw materials, acquisition process, handling, labeling and requirements related to package, as well as the complaint and disapproval procedures, must be discussed between the manufacturer and the suppliers. 13.2.3 For every delivery of containers with raw material, the packages and the seal integrity and the relation between the requisition, the invoice from supplier and the labels of the product, which must be into the container, must be verified. 13.2.4 All the raw material received must be verified in order to ensure that the delivery is according to the requisition. The packages must be externally clean and, whenever required, labeled with the related data. 13.2.5 The containers damages or any other problem which might affect the raw material quality must be recorded and reported to the quality control department, and they must be investigated.

13.2.6 If a single raw material shipment presents different batches, each batch must be considered separately to sampling and release essays. 13.2.7 The raw materials placed in the storage area must be appropriately identified. The labels must present, at least, the following information: (a) name of the raw material and the related internal reference code, if the company has an established system; (b) batch number designated by the manufacturer/supplier and the number given by the company when it is received; (c) raw material status in storage (quarantined, under analysis, approved, reproved, returned); (d) date of manufacturing, expiration date, and whenever applicable, the date of reanalysis; (e) manufacturer, origin and source of the raw material. 13.2.8 The identification by a validated electronic system is allowed. In this case, it is not necessary to show all the information described above on the label. 13.2.9 Procedures ensuring the identification of the content of each raw material container must be used. The containers from where the samples are taken, must be identified. 13.2.10 Only the raw material released by the quality control department and that are within the respective expiration dates must be used. 13.2.11 The raw materials must be fractioned only by the indicated employees, according to written procedures. The raw materials must be carefully weighed or measured, in clean and correctly identified containers. 13.2.12 The fractioned raw materials, as well as their weights or volumes, must be checked by another employee and the checking must be recorded. 13.2.13 The fractioned raw materials for each production batch must be kept together and visibly identified as such. 13.3 Packaging materials 13.3.1 The acquirement, handling, and quality control of the primary, secondary packaging materials and printed materials must be performed the same way as with the raw materials. 13.3.2 The printed materials must be stored under safe conditions, in order to avoid the possibility of unauthorized accesses. The labels and other reproved printed materials must be kept and transported, safely and duly identified, before their destruction. There must be a record of the printed materials destruction. 13.3.3 Every batch of printed material and packaging material must receive a specific reference number or identification mark. 13.3.4 The printed materials, for primary or secondary packages, old and obsolete must be destroyed and this procedure must be recorded. 13.3.5 All the package materials to be used must be checked as for quantity, identification and conformity with the package instructions, at the moment they are delivered. 13.4 Intermediary products and bulk products 13.4.1 The intermediary products and the bulk products must be kept under specified conditions determined for each product. 13.4.2 The intermediary products and the bulk products acquired must be handled upon receiving just as raw materials. 13.5 Finished products 13.5.1 The introduction of part or the totality of the previous batches produced, meeting the quality standards required, to another batch of the same product, at a certain stage of manufacturing, must be previously authorized and performed according to the defined procedures, after the evaluation of the risks involved, including any possible effect on the expiration date. The process must be recorded. 13.5.2 The finished products must be kept in quarantine until they are finally released by the quality control. Then, they must be stored as available stock, according to the conditions established by the manufacturer. 13.6 Reproved and returned materials and products.

13.6.1 The reproved materials and products must be identified as such and stored separately, into restricted areas. They may be returned to the suppliers, reprocessed, or destroyed. The action adopted must be approved by the Authorized Person and duly recorded. 13.6.2 The reproved products reprocessing can only be allowed if the finished product quality is not affected, if the specifications are met and if the operation is performed according to authorized procedures and defined after the evaluation of the risks involved. A record of the reprocessing must be kept. Any reprocessed batch must receive an identification that allows its tracking. 13.6.3 The Quality Control must perform additional essays to any finished product that has been reprocessed, or that has been incorporated to a certain recovered product. 13.7 Collected products 13.7.1 The products collected from market must be identified and stored separately in a safe area, until its destination is defined. The final decision must be taken as soon as possible. 13.8 Returned products 13.8.1 The products returned by the market must be identified and stored separately in a safe area until their destination is defined. Only after a critical evaluation by the Quality Control, according to written procedures, these product may be considered to resale, repackaging or incorporation into another posterior batch bulk. The nature of the product, as well as any special storage conditions required, its conditions, background and running time since its expedition until devolution, must be taken into account in the evaluation above mentioned. 13.8.2 When there is any doubt as for the product quality, this must not be considered appropriate to be incorporated or reused. In this case, if possible, a chemical reprocessing may be performed to recover the active substance. Every action must be duly recorded. 13.9 Reagents and means of culture 13.9.1 All the reagents and means of culture must be registered when received or prepared. 13.9.2 The prepared reagents must be elaborated according to written procedures and properly labeled. The label must indicate the concentration, date of preparation, standard factor, expiration date, date for new standardization and storage conditions. The label must be signed and dated by the person who prepared the reagent. 13.9.3 Positive controls must be done, as well as negative controls, so the adequacy of the means of culture may be checked. The size of the inoculum used in positive controls must be appropriate to the required sensitivity. 13.10 Reference standards 13.10.1 The reference standards may be available as official reference standards. The secondary references, work references, prepared by the manufacturer must be checked and released, and then, kept just as the official standards. Besides, they must be kept under the responsibility of a designee, in a safe area. 13.10.2 The official reference standards must only be used for the purposes described in the monograph. 13.10.3 The secondary or work standards may be checked upon the appropriate verification essays, at regular periods, in order to ensure the standardization. All the secondary reference standards must be based in official reference standards. 13.10.4 All the reference standards must be kept and used in a way that does not affect their quality. 13.11 Waste materials 13.11.1 Actions must be taken in relation to the appropriate and safe keeping of waste materials to be eliminated. The toxic substances must be kept in restrict access locations. The inflammable materials must be kept in separated locations, designed to this purpose, as required by the current legislation.

13.11.2 The waste material must not be accumulated. It must be collected into appropriate containers, in a specific place, and they must be safely and sanitarily disposed, regularly and frequently. 13.12 Different materials 13.12.1 It must not be allowed that raticides, insecticides, fumigating agents and sanitizing materials contaminate the equipment, raw materials, package materials, in-process materials and finished products. Documentation The documentation is an essential part of the Quality Assurance system and it must be related to all of the GMP aspects. Its purpose is to define the specifications of all the materials and manufacturing methods and control, in order to ensure that all the personnel involved in the manufacturing may decide what to do and when. Besides, its purpose is to ensure that the Authorized Person has all the information required to decide whether to release or not a certain drug batch to be sold, and it also makes possible a tracking to investigate the background of any batch suspicious of quality deviation. All the documents may be gathered in only one folder, or they may be kept separated, easily available, constituting the manufacturing batch record. 14.1 General aspects 14.1.1 The documents must be written, revised and delivered only to designees. They must cover all the manufacturing steps, authorized by the registration. 14.1.2 Original documents must be approved, signed and dated by the designee. Any document must be modified without previous authorization. 14.1.3 The documents contents cannot be ambiguous: its title, nature and purpose must be clearly, accurately and correctly presented. Besides, they must be placed in order and easy to check. Reproduced documents must be legible and have their truth guaranteed in relation to the original. 14.1.4 The documents must be regularly revised and updated. When a document is revised, there must be a system to avoid the misuse of the replaced version. 14.1.5 When documents require the entry of data, they must be clear, legible and indelible. There must be space enough left to every data entry. 14.1.6 All the changes done in any document must be signed and dated, the change must allow the reading of the original information. When applicable, the reason for the change must be recorded. 14.1.7 A record must be kept on all the performed or finished actions, in a way that all the significant activities related to the manufacturing of drugs, may be tracked. All the records, including the ones related to the Standard Operation Procedure (SOP) must be kept for, at least, a year after the expiration date of the finished product. 14.1.8 The data may be recorded by an electronic processing system or by photography or other trustful means. The master formulas/standard formulas and the Standard Operation Procedures - SOPs - related to the system being used, must be available, as well as the accuracy of the data recorded must be checked. If the data records is done by an electronic processing, only designees may change the data in the computers. There must be a record of the changes performed. The access to the computers must be restricted by keywords or other means. The entry of data considered critical must be checked by another designee. The electronic records of the batch data, must be protected by transferring copies into magnetic tapes, microfilm, paper impression or other means. It is specially important that, during the retention period, the data are readily available. 14.2 Labels 14.2.1 The identification placed in containers, equipment, installations and products must be clear, unambiguous and in a format approved by the company, presenting the necessary data. Besides text, different colors to indicate the product status may also be used (e.g.: quarantined, approved, reproved, clean). 14.2.2 All the finished products must be identified by labels, according to the required by the current sanitary legislation.

14.2.3 The reference standard labels and the documents following them must indicate the concentration, date of manufacturing, and expiration date, the date when the seal was broken and the storage conditions, when appropriate. 14.3 Specifications and quality control essay procedures 14.3.1 The procedures of the quality control essays described in the document must be validated taking into account the premises and equipments available, before they are adopted as a routine. 14.3.2 All the specifications must be duly authorized and dated, in relation to the identification, content, purity and quality essays of raw materials, packaging materials and finished products. Besides, essays must be performed in the intermediary and the bulk products. There must be specifications related to the water, solvents and reagents (acids and bases) used in the production. 14.3.3 The essays procedures must be approved and kept by the Quality Control and they must be available in the sites responsible for the performance of the essays. 14.3.4 Periodical revisions of the specifications must be performed in order to be updated according to new issues of the national pharmacopoeia, or other official compendia. 14.3.5 The pharmacopoeia, reference standards, spectrometry references and other necessary reference materials must be available in the quality control laboratory. 14.4 Specifications to raw materials and packaging materials 14.4.1 The specifications of raw materials, primary packaging materials and printed materials must have a description, including, at least: (a) name and internal reference code; (b) reference of the pharmacopoeia monograph, if there is one; and (c) quantitative and qualitative requests with their acceptance limits. 14.4.2 Depending on the practice adopted by the company, other data may be added to the specifications, such as: (a) supplier identification and the original manufacturer of the materials; (b) template of the printed material; (c) orientations about sampling, quality essays and reference used in the control procedures; (d) storage conditions and precautions; (e) maximum storage period before a new exam is performed. 14.4.3 The packaging material must meet the specifications, emphasizing their compatibility with the pharmaceutical product contained. The material must be examined for visible physical and critical damages, as well as for the required specifications. 14.4.4 The documents describing the control essay procedures must indicate the frequency new tests of each raw material must be performed. 14.5 Specifications to intermediary products and bulk products 14.5.1 The intermediary and bulk products specifications must be available every time these materials are acquired or expedited, or if the data on the intermediary product have to be used in the final product evaluation. The specifications must be compatible with the specifications related to raw materials or finished products. 14.6 Specifications to finished products: 14.6.1 The specifications must include: (a) generic name of the product and trademark or commercial name, whenever applicable; (b) name of the active principles with their respective DCB or DCI; (c) formula or its reference; (d) pharmaceutical presentation and package details; (e) references used in sampling and control essays; (f) qualitative and quantitative requests, with their acceptance limits; (g) conditions and precautions to be taken in storage, whenever applicable; (h) expiration date. 14.7 Master formula/ Standard formula

14.7.1 There must be a master formula/standard formula for each product and batch size to be manufactured. 14.7.2 The master formula/standard formula must include: (a) the name of the product with the reference code related to its specification; (b) description of the pharmaceutical presentation, product concentration and batch size; (c) list of all the raw materials to be used (with their respective DCB or DCI); with the quantity used of each one, using the generic name and reference that are unique to each material. Any substance which may disappear along the process must be mentioned; (d) declaration of the expected final yield, with the acceptable limits, and of intermediary yields, when applicable; (e) indication of the processing place and the equipment to be used; (f) methods (or their references) to be used in the preparation of the main equipment, such as cleaning (specially after a product change), assembling, calibration, and sterilization; (g) detailed instructions on the steps to be followed in the production (check of materials, pre-treatments, sequence of materials addition, mixing time, temperature); (h) instructions related to any in-process controls, with their acceptance limits; (i) requirements related to the products packaging, including container, labeling, and any other special storage condition; (j) any special precautions to be observed. 14.8 Packaging instructions 14.8.1 There must be authorized instructions as for the packaging process, related to each product and to the size and type of package. These instructions must include the following data: (a) name of the product; (b) description of its pharmaceutical presentation and application route, when applicable; (c) package dimensions, shown as numbers, weight or volume of the product contained in the final container; (d) complete list of all the package material required to a standard batch size, including quantities, sizes and types, with the code or reference number related to the specifications of each material; (e) sampling or reproduction of the materials used in the packaging process, showing the place where they were printed or engraved, the batch number and its expiration date; (f) special precautions must be observed, such as the attentive examination of equipment and area where the packaging takes place, in order to ensure the absence of printed materials of previous products in the packaging lines; (g) description of the packaging operations, and equipment to be used; (h) details of the in-process controls, together with the sampling instructions and the acceptance limits. 14.9 Records of the production batches 14.9.1 A record must be kept on the production of each batch. These records must be based in the master formula/standard formula approved and in use, avoiding transcription errors. 14.9.2 Before starting a production process, it must be checked if the equipments and the working area are free from previously produced products, as well as the documents and necessary materials to the planned process. Besides, it must be verified if the equipment are clean and appropriate for use. The verification of these items must be recorded. 14.9.3 During the production process, all the steps developed must be recorded, comprehending the initial and final time of execution of each operation and, duly signed and dated by the persons responsible for the performance of each step, ratified by the area supervisor. The records of the production batches must show, at least, the following information: (a) name of the product; (b) number of the batch being manufactured; (c) dates and times of start and end of the main intermediary production steps; (d) name of the person responsible for each production step;

(e) identification of the operators of the different production steps and, when applicable, of the person(s) checking each one of these steps; (f) number of batches and/or the number of analytical control and the quantity of each raw material used, including the batch number and the quantity of any material returned or reprocessed which has been added; (g) any significant operation or event in the production, and the main equipment used; (h) in-process controls performed, the identification of the person(s) performing them and the results obtained; (i) quantities obtained of the product in the different production steps (yielding), together with comments or explanations about any significant deviation of the expected yielding; (j) observations on special problems, including details such as the signed authorization for each change of the manufacturing formula or instructions of production. 14.10 Records of the batches packages 14.10.1 Records of the package of each batch or part of batch must be kept, according to the package instructions. The records must be prepared in a way to avoid transcription errors. 14.10.2 Before any process is started, it must be checked if the equipment and the working area are free from products and documents previously used, if the equipment is clean and appropriate to use. The verification of these aspects must be recorded. 14.10.3 During the packaging process, all the steps involved must be recorded, dated, and signed by the responsible persons and the area supervisor, comprehending the starting time and the ending time of each operation. The records of the manufacturing batches must contain: (a) name of the product, bulk product batch number and quantity to be packed, as well as the number of the finished batch, the final product planned quantity, the actual quantity obtained and the reconciliation; (b) date(s) and time(s) of the packaging operations; (c) name of the person responsible for the packaging operation; (d) identification of the operations in the main steps; (e) verifications performed for the identification and accordance with the packaging instructions, including the results of the in-process controls; (f) details of the packaging operations, including references to equipment, packaging lines used and, when applicable, the instructions and records related to the unpacked products storage; (g) samples of printed packaging materials used, with the batch number, the manufacturing date, when applicable, the expiration date and any additional print; (h) observations about any special problems, including details about any deviation of the instructions provided for the packaging process, with the written authorization of the designee; (i) the quantities of all the printed packaging materials with the reference or identification number and the bulk products delivered to be packaged, used, destroyed or returned to stock and the quantity obtained of the product, in order to perform a correct reconciliation. 14.11 Standard Operation Procedures - SOPs and their records 14.11.1 There must be Standard Operations Procedures and records on the receiving of raw materials and packaging materials. 14.11.1.1 Within the records done in the receiving, the following must be included: (a) name of material described in the invoice and in the containers; (b) internal name and/or code of the material; (c) date of receiving; (d) name of supplier and manufacturer; (e) reference number or batch number indicated by the manufacturer; (f) total quantity and number of containers received; (g) number given to the batch after receiving it;

(h) any significant commentary (status of containers, for instance). 14.11.2 There must be Standard Operation Procedures for internal identification of the products stored in quarantine and released (raw materials, packaging materials and other materials). 14.11.3 There must be Standard Operation Procedures for every instrument or equipment, which must be available near the respective equipment and instrument. 14.11.4 There must be Standard Operation Procedures related to sampling and specifying the designees to collect the samples. 14.11.4.1 The instructions related to sampling must include: (a) method and sampling plan; (b) equipment to be used; (c) any precaution to be observed in the sense of avoiding contamination of the material or any deterioration of its quality; (d) quantity of sample(s) to be taken; (e) instructions when a sample subdivision is required; (f) type of container to be used in the samples packaging, as well as whether the sampling procedures must be performed in aseptic conditions or not; (g) any specific precautions to be observed, specially on the sampling of sterile or hazardous materials; 14.11.5 There must be a Standard Operation Procedure describing the details of the batches numbering system, with the purpose of ensuring that each intermediary product, bulk product, or finished product batch is identified with a specific batch number. 14.11.5.1 The Standard Operation Procedures related to the batches numbering which are applied to the packaging steps must be inter-related. 14.11.5.2 The Standard Operation Procedure related to the batches numbering must ensure that the same batch numbers are not used more than once. This also applies to the reprocessing. 14.11.5.3 The indication of a batch number must be immediately registered. The record must include the date when the mentioned number was indicated, the product identification and the batch size. 14.11.6 There must be written procedures related to the control essays performed in materials and products, in the different manufacturing steps, describing the methods and the equipment to be used. The essays performed must be registered. 14.11.6.1 The analyses records must include, at least, the following data: (a) name of the material or product and, when applicable the pharmaceutical presentation; (b) batch number and, when applicable, manufacturer and/or supplier; (c) references to the analysis procedures; (d) analytical results, including observations, calculations, references used and specifications (limits); (e) date when the essays are performed; (f) identification of the people who performed the essays; (g) identification of the people who checked the essays and the calculations; (h) approval or disapproval declaration (or another decision), dated and signed by the responsible person. 14.11.7 Written procedures must be available as for the approval or disapproval of materials and products and, specially, as for the release for the finished product sale by the authorized person. 14.11.8 Records must be kept on the distribution of each batch of a certain product, in order to make their collection easier, if necessary. 14.11.9 Standard Operation Procedures and developed actions records must be available to the manufacturing activities and when appropriate, the conclusions of the following aspects: assembling and validation of equipment; analytical and calibration apparatus; maintenance, cleaning and sanitization; personal data, including qualification, training, garments and hygiene; environmental management;

plagues control; complaints; collection; returns; 14.11.10 The daily log books must be kept together with the main equipment, and they must register its use, validation, calibration, maintenance, cleaning or repairing operations, including dates and the identification of the person who performed it. 14.11.11 The register of the use of equipment, as well as the areas where they are processed must be done chronologically. 14.11.12 There must be written procedures attributing the responsibilities related to sanitizations and describing, in details, the chronograms, methods, equipment and cleaning materials to be used, as well as premises to be cleaned. The described procedures must be fulfilled. B.- SECOND PART: Good Manufacturing Practices and Quality Control 15. Good manufacturing practices The manufacturing operations must follow the Standard Operation Procedures -SOPs clearly defined and approved, according to the approved Technical Report at the moment of the registration granting before the sanitary authorization in charge, with the purpose of obtaining products within the required quality standards. 15.1 General Aspects 15.1.1 All the handling of materials and products, such as receiving, quarantine, sampling, storage, supply, processing, labeling, and packaging must be performed according to the established and registered procedures and instructions. 15.1.2 Any instruction or procedure deviation must be avoided. If there are deviations, they must be approved, in written, by a designee, with the participation of the Quality Assurance. 15.1.3 The procedures and reconciliation must be checked, in order to ensure that there is no inconsistency beyond the acceptable limits. 15.1.4 The operations performed in different products must not be performed simultaneously or consecutively in the same room, unless the absence of mixing or cross-contamination risk is proved. 15.1.5 During all production period, materials, containers with products, main equipment and rooms used must be duly identified, showing the product or material under process, its concentration (when applicable), and the batch number. Whenever required, it must also show the production step. 15.1.6 The access to the production premises must be restrict to authorized personnel. 15.1.7 The non-pharmaceutical products must not be produced in areas or with equipment designed to the production of drugs. 15.1.8 The in-process controls are, usually, performed in the production areas. They must not present any risk to the product quality. 15.2 Prevention of cross-contamination and microbial contamination in the production. 15.2.1 When powdered materials and products are used, special precautions should be taken to avoid the formation and dissemination of particles. 15.2.2 The contamination of a raw material or a certain product by another material or product must be avoided. The risk of accidental cross-contamination arises from the uncontrolled release of powders, gases, steams, aerosols, or organisms from in-process materials and products, from wastes in the equipment, from the entrance of insects, from the operators garments and their skin, etc. The significance of this risk ranges with the type of contaminant and contaminated product. 15.2.3 Among the most dangerous contaminants, we find the highly sensitizing materials, the biological preparations with organisms in vivo, some hormones, cytotoxic substances and other highly active materials. The products which contamination may cause larger damages to users are the ones administered by parenteral route or applied on open wounds, as well as products administered in large doses and/or for long terms. 15.2.4 The cross-contamination must be avoided through appropriate techniques or organization measures, such as:

(a) production in exclusive and separated premises (which might be necessary for products like vaccines, live bacteriological preparations), separated buildings (penicillin and cephalosporin), in campaign (time separation) in case of damages (fire, flood, etc.) and in emergency situations (war, etc.), in this case followed by a cleaning and decontamination processes, duly validated; (b) use of antechambers, with differences in the air pressure; (c) decrease to the minimum contamination risk caused by re-circulation or reentry of untreated air or poorly treated; (d) protecting garments worn in the areas where the products presenting cross-contamination risk are processed. (e)Use of validated cleaning and decontamination procedures; (f) use of a “closed production system”; (g) wastes essays; (h) use of labels, showing the cleaning status in the equipment. 15.2.5 The efficiency of the measures adopted to prevent the cross-contamination must be periodically verified. This verification must be done in accordance with the Standard Operation Procedures. 15.2.6 The production areas where products susceptible to the contamination by microorganisms are being manufactured must be periodically monitored. 15.3 Production operations: intermediary and bulk products 15.3.1 Before any production operation is started, the necessary actions must be taken so the working areas and equipment are clean and free from any raw material, products, products wastes, labels or documents unnecessary to the new operation to be started. 15.3.2 All the in-process controls and environmental controls must be performed and registered. 15.3.3 Procedures designed to detect failures in equipment or installations (e.g., water, gas) must be adopted. The damaged equipment must be identified as such and must not be used until its failures are corrected. The equipment used in the production must be cleaned according to established procedures. 15.3.4 The containers used in the filling process must be previously cleaned and sterilized, when applicable. Attention must be given to avoid and remove any contaminant. 15.3.5 Any significant deviation of the expected yielding must be investigated and registered. 15.3.6 It must be ensured that the piping or other equipment used to the transportation of products from one area to another are correctly connected. 15.3.7 The pipes used in the purified water for injections transportation must be clean and decontaminated, according to written procedures determining the limits of microbial contamination and measures to be adopted. 15.3.8 The equipment and instruments used in the measuring, weighing, record and control procedures must be subjected to maintenance and calibration at pre-established periods and these operations records must be kept. In order to ensure a satisfactory functioning, the instruments must be daily identified, or before they are used for analytical essays. The dates of calibration, maintenance and when the future calibrations must be performed, must be clearly established and registered. 15.3.9 The repairing and maintenance operations must not present risk to the quality of the products. 15.4 Packaging operations 15.4.1 In the packaging operations schedule, special attention must be given to the procedures that minimize the risks of cross-contamination, mixings or replacements. Different products must not be packaged next to each other, unless there is a physical separation or electronic controls are applied. 15.4.2 Before starting the packaging operations, measures to ensure that the working areas, packaging lines, printing machines and other equipment are clean and free from any product or material used previously and that is no longer needed to the new operation to be started must

be adopted. The liberation of the packaging line must be done upon an appropriate inspection and it must be recorded. 15.4.3 The name and batch number of the in-process product must be shown in each packaging step or in the packaging line. 15.4.4 The filling and closing steps must be immediately followed by labeling. If this is not possible, appropriate procedures must be applied to endure that there is no mixings or labeling errors. 15.4.5 The correct performance of the printing operations, done separately or along the packaging process, must be checked. A greater attention must be given to manual printings, which must be checked at regular periods. 15.4.6 In order to avoid mixing/exchange special cares must be taken, when detached labels are used or when large amounts of printings are done out of the packaging line, as well as when manual packaging operations are adopted. The checking of all the labels within the packaging line using electronic controls may be useful to avoid mixings. However, the electronic code readers, label counters and similar instruments must also be checked in order to see if they are working properly. 15.4.7 The information printed and engraved in relief in the packaging materials must be clear and resistant to wastage and adulteration. 15.4.8 The product line inspection during the packaging must include, at least, the following verifications: (a) general aspect of packages; (b) if the packages are complete; (c) if the correct products and packaging materials are being used; (d) if the printings are correct; (e) the correct functioning of the packaging line monitors. 15.4.9 The samples taken for in-line inspection must not return to packaging process, without a proper evaluation. 15.4.10 The products involved in abnormal occurrences during the packaging procedure, must only be reintroduced after subjected to inspection, investigation and approval by a designee. A detailed record of this operation must be kept. 15.4.11 Any inconsistency, significant or uncommon, observed during the reconciliation of the quantity of the bulk product, of the printed packaging materials and the number of units packaged, must be investigated and satisfactorily identified before the release of the product batch. 15.4.12 After the conclusion of each operation, all the codified package material with the batch number that will not be used must be destroyed, and the destruction process must be recorded. To return the non-codified printed material to stock, written procedures must be followed. 16. Good quality control practices The Quality Control is responsible for the activities related to sampling, specifications and essays, as well as the organization, documentation and release procedures guaranteeing that the necessary and essential essays are performed and that the materials are not released to use, neither the finished products released to be sold or supplied, until its quality has been considered satisfactory. The Quality Control must not summarize to laboratory operations, it must also take part and be involved in all the decisions which might be related to the product quality. The independency of the quality control from the production is considered essential. 16.1 Control of raw materials, intermediary, bulk and finished products 16.1.1 All the essays must follow the instructions established by written procedures and approved for each material or product. The result must be checked by the supervisor before the materials or products are released or reproved. 16.1.2 The samples must be taken, according to written and approved procedures and be batch representative.

16.1.3 The sampling must be performed in a way to avoid the occurrence of contamination or other adverse effects on the quality of the product sampled. The containers sampled must be identified and carefully closed after sampling. 16.1.4 During the sampling care must be taken to avoid contaminations or mixtures of the material that is being sampled. All the equipment used in the sampling process which have contact with the materials must be clean. Some particularly dangerous or strong materials may require special precautions. 16.1.5 The equipment used in the sampling must be clean and, if required, sterilized before and after each use and kept separated from the other laboratory equipment. 16.1.6 Each container with sample must be identified and show the following information: (a) name of the sampled material; (b) batch number; (c) number of the container sampled; (d) signature of the person taking the sample; and (e) date when the sample was taken. 16.2 Necessary essays 16.2.1 Raw materials and package materials 16.2.1.1 Before releasing the raw materials and the package materials for use, the person responsible for the Quality Control must ensure that they are tested as for the conformity with the identification, strength, purity specifications and other quality parameters. 16.2.1.2 Identification essays must be performed in the samples taken from each raw material container. If SPGV manufacturers, the content identification test must be performed in a statistical sample from the excipients, provided that the supplier is qualified. 16.2.1.3 Each printed material batch to be used in the packaging process must be evaluated after being received. 16.2.1.4 The manufacturer may accept the certificate of analysis issued by the supplier, provided that its trustful is established through a periodical validation of the presented results and through audits at the premises. This does not exclude the need to perform the identity test. The certificates issued by the supplier must be original and its authenticity ensured. They must show the following information: (a) supplier identification, signature of the responsible employee; (b) name and number of the tested material batch; (c) description of the specifications and methods used; and (d) description of the results of the essays and the date when they were performed. 16.3 In-process control 16.3.1 There must be records on the in-process control, which must be part of the batches record. 16.4 Finished products 16.4.1 Before released the pharmaceutical products batches must have their accordance with the established specifications guaranteed, upon laboratory essays. 16.4.2 The products not meeting the established specifications must be reproved. If viable, they may be reprocessed. However, the reprocessed products must meet all the specifications and quality criteria before being approved and released. 16.5 Revision of the production records 16.5.1 The production and control records must be revised. If a certain batch does not meet the specifications or presents any divergence, it must be investigated. If required, the investigation must be extended to the other batches of the same product or of other products which might be related to the detected deviation. There must be a record of the investigation, where the conclusion and the necessary follow-up actions are presented. 16.5.2 The sample taken from each finished product batch must be kept for, at least twelve (12) months after the expiration date, except for Large Volume Parenteral Solutions (SPGV), which must be kept for, at least, thirty (30) days after the expiration date. Usually, the finished products must be kept in their final package and stored under the recommended conditions. If the

packages are large, exceptionally the samples may be kept in smaller containers with the same characteristics and stored under the recommended conditions. 16.5.3 The active substances samples must be kept for, at least, one year after the expiration date of the final products which originated. Samples from other raw materials (excipients), except for solvents, gases and water, must be kept for the minimum period of two years, if allowed by the respective stability studies performed by the raw material manufacturer. The quantities of samples of materials and detained products must be sufficient to make, at least, two complete reanalysis possible. 16.6 Stability study 16.6.1 The Quality Control must evaluate the quality and stability of the finished products and, whenever required, of the raw materials, intermediary and bulk products. 16.6.2 The Quality Control must establish the expiration dates and the specifications related to the expiration date, based on stability essays performed in accordance with the storage conditions. 16.6.3 A written program of stability study must be developed and implemented, including the following elements: (a) complete description of the product involved in the study; (b) all the methods and essays parameters, which must describe the procedures of the strength, purity and physical characteristics essays, as well as documented evidence that the essays performed indicate the product stability; (c) prevision related to the inclusion of a sufficient number of batches; (d) essay chronogram for each product; (e) instructions on the special storage conditions; (f) instructions related to the appropriate detention of samples; and (g) a summary of all the data obtained, including the evaluation and the study conclusions. 16.6.4 The stability of a product must be determined before its marketing and it must be repeated after any significant change in the production processes, equipment, packaging materials, etc. C. - THIRD PART: Supplementary guidelines 17. Sterile products The guidelines presented herein does not replace any section from the first or the second parts, but reinforce specific points on the manufacturing of sterile preparations, in order to minimize the contamination risks by viable or non-viable particles or by pyrogenic substances. 17.1 General considerations 17.1.1 The sterile preparations production must be done in clean area, which personnel and materials entry must be done through passage chambers. The areas must be kept within the appropriate cleanliness standards and, they must have ventilation systems with filters of proved efficiency. 17.1.2 The many operations involved in the preparation of materials (such as containers and buffers), preparation of the product, filling and sterilization must be performed in separated areas within the clean area. 17.1.3 The clean areas used in the manufacturing of sterile products are classified, according to the characteristics required for the quality of air, in grades A, B, C and D (see Table 1). TABLE 1 Air classification system for the production of sterile products a

At rest In operation Maximum number allowed of

particles/m3 Maximum number allowed of

particles/m3 Grade

0.5-5.0 µm Above 5.0 µm 0.5-5.0 µm Above 5.0 µm

A* 3 500 0 3 500 0 B 3 500 0 350 000 2 000 C 350 000 2 000 3 500 000 20 000 D 3 500 000 20 000 Undefined Undefined

a Source: WHO Technical Report Series, No. 902, 2002 17.1.4 To obtain air with the required characteristics, specific methods must be used and it must be observed that: (a) the air laminar flow system must have a homogeneous speed of about 0.30 m/s, in case of vertical flow, and 0.45 m/s in case of horizontal flow. The speed accuracy of the air flow depends on the type of equipment. (b) to achieve grades B, C and D, the total number of air exchange of the area, usually must be superior to 20 exchanges per hour, in a room with the appropriate standard of air flow with filters HEPA (High Efficiency Particulate Air); (c) the size of the air samples must be large and sufficient, in order to make the low contamination determination trustful. (d) The different air particle classification systems for clean areas are presented on Table 2. (e) There may be difficulty to demonstrate the accordance to the air classification in the filling point, during this operation, due to the formation of particles/droplets arising from the product itself. 17.1.5 Each production operation required a determined purity level of the air to minimize the risks of contamination by particles or microorganisms in the products or materials handled. The levels of particles or microorganisms presented on Table 1 must be kept next to the product, everytime it is exposed to the environment. These conditions must also be respected in all of the surrounding areas. 17.1.6 If, for any reason, the air conditions in the working area are not kept in accordance with the pre-established conditions, a cleaning/sanitization procedure must be performed to achieve the appropriate conditions. 17.1.7 The use of the absolute barrier technology (closed systems) and automate systems to minimize the human intervention in the production areas may bring advantages to the maintenance of the manufactured products sterility. When these techniques are used, the recommendations related to the air quality and its management must be applied and the appropriate interpretation of the words “working place” and “environment” must be done. 17.2 Sterile products production 17.2.1 The production operations are divided, herein, into three categories: First - when the product is filled and closed in its primary container and then sterilized; Second - when the product is sterilized by filtration and filled into previously sterilized containers; Third - when the product cannot be sterilized by filtration neither by final sterilization, consequently it has to be produced from sterile raw materials and filled aseptically into previously sterilized containers. 17.2.2 The grades of each production area are specified on items 17.3, 17.4, and 17.5 and must be selected by the manufacturer based on the type of product and the correspondent validations. 17.3 Products with final sterilization 17.3.1 In general, the solutions must be prepared in areas presenting grade C, to a low initial counting of microorganisms and particles, creating the appropriate conditions to the immediate filtration and sterilization. The solutions preparation may be performed in grade D environments, if additional measures to minimize contamination, such as the use of closed containers, are taken.

17.3.2 In case of parenteral solutions, the filling must be done under a laminar air flow (grade A), installed in a grade C area. The preparation of other sterile products, i.e., ointments, creams, suspensions and emulsions, as well as the filling of the respective containers usually must be conducted in a grade C environment, before final sterilization. 17.4 Products sterilized by filtration 17.4.1 The handling of raw materials and the preparation of solutions must be performed in grade C areas. If additional measures are taken to minimize contamination, such as the use of closed containers before filtration, these activities may be performed in a grade D environment. After filtration, the product must be handled in a grade A or B area, surrounded by grade B or C, respectively. 17.5 Sterile products prepared from sterile raw materials, in aseptic conditions 17.5.1 The handling of raw materials and all the additional processing must be done in grade A or B areas, surrounded by grade B or C areas, respectively. 17.6 Personnel 17.6.1 During the development of the aseptic processes, it is essential that the minimum personnel required is in the clean areas. If possible, the inspections and controls must be performed outside these areas. 17.6.2 All personnel (including cleaning and maintenance staff) developing activities in these areas must receive regular training on the issues significant to the sterile products production, including the mention of personal hygiene and basic concepts of microbiology issues. If required, the entrance of people not trained in these areas (i.e., people hired for construction or maintenance), special cares must be taken in relation to their supervision. 17.6.3 The employees taking part in activities related to the production of products in animal tissue substrate or microorganisms cultures different from the ones used in the manufacturing process in course, must not enter the production areas of sterile products, unless previously established decontamination procedures are applied. 17.6.4 The adoption of high standards on personal hygiene and cleaning is essential. People involved in the manufacturing of drugs must be instructed to communicate their superior of any change in their health condition, which might contribute to the dissemination of contaminants. It is convenient to perform periodic health examinations. The actions to be taken in relation to the people which might be introducing improper microbiological risks must be taken by people in charge designated to it. 17.6.5 The personal clothes must not be brought into the clean areas. People entering the lockers of these areas must already be wearing the standard uniforms of the manufacturing site. The clothes changing and hygiene processes must follow written procedures. 17.6.6 The garments and their quality must be adapted to the process and working area. Besides, it must be wore in order to protect the product from contaminations. 17.6.7 Wristwatches and jewelry must not be worn in the clean areas, as well as cosmetic products. 17.6.8 The garments worn must be appropriate to the classification of the clean area where the personnel is working, and the following must be observed: Grade D: Hair and beard must be covered. Protecting garments and shoes, or shoe protectors, proper for the are must be worn. Appropriate measures must be taken in order to avoid any contamination from external areas. Grade C: Hair and beard must be covered. Appropriate garments, tightened around the pulse and with turtle neck must be worn. The garment may not have loose fibers or particles. Besides, shoes or shoe protectors proper for the area must be worn. Grade B: A hood covering all the hair and beard, with its inferior border inside the garments must be worn. A mask must be used on the face, in order to avoid sweat drops to spread. Sterilized gloves, with no talc, disinfected or sterilized boots must also be worn. The pants hem must be placed inside the boots, as well as the sleeves must be placed inside the gloves. The protecting garment must not loose any fiber or particle and it must detain the particles released by the body of whom wears it.

17.6.9 All employees working in grades B and C rooms must receive clean and sterilized garments at each working shift. Gloves must be regularly disinfected during operations, as well as the masks and gloves exchanged at each working shift. 17.6.10 The garments worn in the clean areas must be washed and cleansed to avoid the release of contaminants in the areas where they will be worn. It is convenient to have a laundry uniquely for this kind of garments. Garments damaged by usage may increase the risk of releasing particles. The cleaning and sterilization operations must follow the Standard Operation Procedures- SOPs. 17.7 Premises 17.7.1 All the premises must be designed in a way to avoid the unnecessary entrance of the supervision and control staff. The grade B areas must be designed in a way that all the operations may be observed from outside. 17.7.2 In the clean areas, all the surfaces exposed must be plain, impermeable, in order to avoid the accumulation or release of particles or microorganisms, allowing the repeated application of cleaning and disinfecting agents, when applicable. 17.7.3 In order to decrease the dust accumulation and to make the cleaning easier, in the clean areas there must not be surfaces which may not be cleaned. The installations must have the minimum of projections, shelves, cupboards and equipment. The doors must also be designed in a way to avoid surfaces which may not be cleansed; sliding doors must not be used. 17.7.4 The coating must be sealed in a way to avoid contamination from the space above them. 17.7.5 The pipes and ducts must be installed in a way to avoid spaces difficult to clean. 17.7.6 The sinks and drains must be avoided, whenever possible, and there must not be areas sinks and drains in the areas where aseptic operations are being performed. When their installation is required, they must be designed, placed and maintained in a way to minimize the risk microbial contamination, it must have efficient siphons, easy to be cleaned and appropriate to avoid air and liquids refluxes. The ground drainage channels, if there is any, must be open, easy to clean and be connected to external drains in a way that the introduction of microbial contaminants is avoided. 17.7.7 The locker rooms in the clean areas must be designed as closed antechambers and used in a way to allow the separation of the different garments changing steps, thus minimizing the microbial contamination and particles from the protecting garments. Besides, the locker rooms must be efficiently insufflated with filtered air. The use of separated locker rooms for entry and exit may be necessary in some occasions. The premises designed to the hygiene of hands, must be located only in the locker rooms, never where the aseptic operations are performed. 17.7.8 The doors of the antechamber cannot be simultaneously opened, and there must be a system to avoid this. There must be an alarm system, sonorous and/or lightening, alerting to the situation mentioned above. 17.8 Equipment 17.8.1 The clean areas must have a ventilation system which insufflates the filtered air and maintains a positive pressure of the area, compared to the surrounding areas. The ventilation must be efficient and appropriate to the required conditions. Special attention must be given to the areas presenting a higher risk, where the filtered air is in contact with the products and clean components. 17.8.2 It may be necessary that the many recommendations related to the air supply and the differential pressure are changed in case of the need to detain pathogenic materials, highly toxic, radioactive materials or bacterial and live virus materials. 17.8.3 In some processes, it may be required the use of premises designed to decontamination and the treatment of air leaving the clean area. 17.8.4 It must be shown that the air system does not constitute a contamination risk. It must be ensured that it does not allow the dissemination of particles from people, equipment or operations, to the production areas at higher risk.

17.8.5 An alarm system must be installed to indicate failures in the ventilation system. Besides, a differential pressure index must be placed between the areas where this difference is important. The pressure differences must be recorded. 17.8.6 The unnecessary access of material and people at the critic areas (grades B and C) must be avoided. Whenever required, it must be done through physical barriers. 17.8.7 Transporting tracks interconnecting grade B clean areas to areas presenting an inferior air classification grade must not be used, unless the track is continuously sterilized (e.g.: an sterilizing tunnel). 17.8.8 The equipments used in the sterile products production, must be chosen in order to be sterilized by steam, dry heat or other method. 17.8.9 Whenever possible, the equipment and utilities disposition must be designed and installed in a way that the maintenance and repairing operations may be performed from the outer side of the clean areas. The equipment that has to be removed for maintenance must be sterilized again after they are reassembled. 17.8.10 When the equipment maintenance is performed into de clean areas, the instruments and tools used must also be clean/disinfected. If the required cleaning and/or asepsis standards are not kept during the maintenance service, the areas must be disinfected, so the production may be restarted. 17.8.11 All the equipment, including sterilizers, air filtration systems and the water production systems, must be subjected to a periodic maintenance plan, validation and monitoring. The approval to the use of equipment must be documented, after the maintenance service. 17.8.12 The installations to be used for quality purified water production for injection must be designed and maintained in a way to ensure the trustful production of water, of appropriate quality. The system must not be operated beyond its installed capacity. The quality purified water for injection must be produced, stored and distributed, according to the procedures ensuring the maintenance of its characteristics, avoiding the proliferation of microorganisms. 17.9 Sanitization 17.9.1 The sanitization of the clean areas constitutes a particularly important aspect. These areas must be frequently cleaned and sanitized according to a specific schedule approved by the Quality Assurance. When using disinfectants, more than one kind must be used, with frequent changes. Periodically, the management of the disinfectant used must be performed to prove that there is not the development of resistant microorganisms. Viewing the limited efficacy of ultraviolet radiation, it must not be used as a substitute in the chemical disinfecting operations. 17.9.2 The disinfectants and detergents must be kept into previously cleaned containers and must not be kept for long terms, unless they are sterilized. The partially emptied containers must not be completed. 17.9.3 The fumigation of clean areas may be useful to reduce the microbial contamination into inaccessible places. 17.9.4 The conditions of the clean areas must be monitored at pre-established periods during the production operations, through the counting of viable particles in the air and surfaces (microbiological). When aseptic operations are developed, the monitoring must be done more frequently in to ensure that the environment is within the specifications. 17.9.5 The results of the monitoring must be taken into account when the batches are evaluated for its approval. The quality of air in relation to the number of particles must also be regularly evaluated. In some moments, when there is no production operation (after the maintenance, validation, cleaning or fumigation processes) there might be the need of an additional monitoring. 17.10 Production 17.10.1 Precautions must be taken in the sense of minimizing the contamination during all the production steps.

17.10.2 The microbiological products with live organisms cannot be produced or filled in the areas used for the production of other drugs. On the other hand, vaccines produced from inactivated microorganisms or bacterial extracts may be filled, after their inactivation in the same premises as other drugs, provided that the inactivation and cleaning procedures are validated. 17.10.3 The use of means of culture favoring the microbial growth in essays to simulate aseptic operations (fillings with sterile means) constitutes an important procedure in the validation of a aseptic filling process. These essays must present the following characteristics: (a) they must simulate as faithful as possible the actual operations, taking into account factors such as the complexity of operations, the number of people involved in the operation and the term of filling; (b) the mean selected must be able to promote the growth of a large number of microorganisms, including those ones likely to be found in the environment where the filling process is performed; (c) they must include the sufficient number of production units to check a high grade of safety detecting lower levels of contamination. The inclusion of at least 3,000 production units is recommended in each filling essay with the nutrient soap. The ideal growth percentage is of 0%; and it must never be higher than 0.1% of contaminated units. All contaminations must be investigated; (d) the fillings with means of culture must be repeated at regular periods and every time there is a significant change in the premises, equipment or process, a new validation must be done. 17.10.4 Care must be taken so the validation processes do not have a negative influence on the production processes. 17.10.5 The activities developed in the clean areas must be as minimum as possible, specially when aseptic operations are being performed. The people’s moves must be methodic and controlled, with the purpose of avoiding the excessive loose of particles and microorganisms. 17.10.6 The raw materials specifications must also include requirements as for the microbial quality. The microbial contamination of the raw materials must be minimum, and the bioload must be monitored before sterilization. 17.10.7 The presence of containers and materials arising particles in the clean areas must be reduced at a minimum and completely avoided when an aseptic work is being performed. 17.10.8 After the final cleaning or sterilization process, the handling of components, containers, bulk products and equipment must be done in a way to avoid that they contaminate again. Each step of the processing of components, containers for bulk products and equipment must be properly identified. 17.10.9 The period between washing, drying and sterilization of components, bulk products containers and equipment, as well as the period between sterilization and use, must be as shorter as possible and it must be subjected to an appropriate limited time to the storage conditions. 17.10.10 The period between the start of the preparation of a certain solution and its sterilization or filtration through a bacterial retention filter, must be as short as possible. A maximum period allowed must be established to each product, taking into account its composition and the recommended storage method. 17.10.11 All the gas destined to help in the filtration or filling process of solutions must go through a sterilizing filter. 17.10.12 The microbiological contamination of products (bioload) must be minimum before the sterilization process. A maximum contamination limit must be established before sterilization, related to the efficiency of the method that will be used and the risk of contamination by pyrogenic substances. 17.10.13 All the solutions, specially large volume parenteral solutions must be filtered, by sterilizing filters, if possible, immediately after its filling process.

17.10.14 When aqueous solutions are placed into sealed containers, the compensatory pressure openings must be protected with hydrophobic filters which prevent the passage of microorganisms. 17.10.15 The components, bulk product containers, equipment and/or any other articles required in the clean area, where aseptic activities are being developed, must be sterilized and, whenever possible, by double door sterilizers in the wall. Other procedures used with the purpose of not introducing contaminants into the clean area, may be accepted under some circumstances (e.g., triple cover). 17.10.16 Any new manufacturing procedure must be validated for proving its efficacy. The validation must be repeated at regular periods or when significant changes in the process or equipment are done. 17.10.17 The water provision sources, the water treatment equipment and the treated water must be regularly monitored, as for the presence of chemical and microbial contaminants, and, when applicable, a control for endotoxins (biological contamination) must also be performed, to check if the water meets the appropriate specifications for its use. Records of the results of the monitoring and measures adopted must be kept. 17.11 Sterilization 17.11.1 The sterilization may be done upon dry or humid heat application, gas agents, sterilizing filtration with a subsequent aseptic filling of the final sterile containers, or by ionizing radiation. Each method has its applications and specific limitations. Whenever possible and viable, the method choice must be the sterilization by heat. 17.11.2 All the sterilization processes must be validated. The sterilization process must correspond to the one stated in the technical report of the Product Registration. 17.11.3 Before the adoption of any sterilization method, its efficacy and adequacy must be proven, so to the desired sterilization conditions are achieved in all the points of each type of load to be processed. This validation must be repeated periodically, at least once a year, and every time significant changes in the load to be sterilized or equipment is done. The results must be recorded. 17.11.4 The biological indicators must be considered just as an additional method of monitoring the sterilization processes. If they are used, strict precautions must be taken to avoid the transfer of microbial contamination from them. 17.11.5 Clear means to differentiate the products and materials sterilized from the non-sterilized ones must be established. Each container, tray or other kind of products or materials transporter must be visibly identified with the material or product name, its batch number and the indication if it was sterilized or not. When appropriate, indicators such as autoclave tape may be used, in order to indicate if a certain batch was subjected to sterilization process or not. But, these types of indicators do not provide trustful information proving that the batch was really sterilized. 17.12 Sterilization by heat 17.12.1 Each heat sterilization run must be recorded with appropriate equipment, accurately and trustfully, (e.g.: time/temperature graphic with the a sufficiently broad range). The temperature must be recorded from a lead-line placed in the coldest point of the sterilization chamber. This point is determined during the validation process. The record system adopted for the sterilization run must be part of the batch documentation. Chemical and biological indicators may also be used, but they must not replace the physical controls. 17.12.2 Enough time must be given for all the load to reach the required temperature, before the sterilization time measures are started. This time must be determined for each type of load to be processed. 17.12.3 After the maximum temperature phase of the sterilization run by heat, the required precautions must be taken in order to avoid the contamination of the sterilized load, during the cooling phase.

17.12.4 No fluid or gas used in the cooling phase may be in contact with the sterilized product, unless it is shown that any container presenting holes or micro-holes will not be approved for use. 17.13 Sterilization by humid heat 17.13.1 The sterilization by humid heat is indicated in the case of materials permeable to water steam and aqueous solutions. The temperature and pressure must be used to monitor the process, the lead-line of the temperature indicator must be independent of the lead-line used by the autoclave controller, and there must be a temperature indicator, which reading during the sterilization process must be routinely verified, by comparison with the values obtained in the graphic. If the autoclaves have a drain at the lowest part of the sterilization chamber, it is also necessary to register the temperature of this position during all the sterilization process. When a vacuum phase is part of the sterilization run, periodical controls on the chamber air-tightness must be performed. 17.13.2 The sterilized materials to be used (when they are not products into sealed containers) must be wrapped in materials which allow the removal of air and the enter of steam, and also avoid the recontamination after sterilization. All the parts of the load of the autoclave must be in contact with the saturated steam or with the water, at the required temperature and during all the time established. 17.13.3 It must be ensured that the steam used in the sterilization meets the appropriate quality to the process and does not contain quarantined additives which might cause contaminations of the product or equipment. 17.14 Sterilization by dry heat 17.14.1 The sterilization process by dry heat must include the forced circulation of air inside the sterilization chamber and the maintenance of a positive pressure, in order to avoid the entry of non-sterile air. If air is inserted into the chamber, it must be filtered through a sterilizing filter. When the sterilization process by dry heat is also used for the removal of pyrogenics, essays using endotoxins must be performed as part of validation. 17.15 Sterilization by radiation 17.15.1 The sterilization by radiation is mainly used with materials and products sensitive to heat. On the other hand, many drugs and some packaging materials are sensitive to radiation. Therefore, this method must only be applied when there is no damaging effect to the product, experimentally proved. The ultraviolet radiation is not an acceptable method of sterilization. 17.15.2 If the sterilization by radiation is performed through an agreement with third parties, the manufacturer have the responsibility of guaranteeing that the requirements established are met and that the sterilization process is validated. 17.15.3 During the sterilization process the radiation doses used must be measured. With this purpose, dosimeters which are independent from the amount of dose applied and which indicate the real amount of radiation doses received by the product must be used. The dosimeters must be included in the load in a number sufficient and so close one from the others that they allow to ensure that there is always a dosimeter in the radiation chamber. When plastic dosimeters are used, they must be used within a time limit established after their calibrations, as well as the values readings must be performed as close as possible of the radiation incidence. The biological indicators may only be used as an additional control mean. 17.15.4 Colored disks sensitive to radiation may be used to differentiate the packages subjected to radiation from the ones not subjected; These disks may not be considered as indicators of sterility guarantee. All the information obtained during the process must be registered in the batch documentation. 17.15.5 The validation methods of the processes used must ensure that the effects of the ranges of the packaging material densities were considered. 17.15.5 The procedures for the handling of materials must ensure that there is no possibility of missing irradiated products with non-irradiated ones. Each package must have an indicator sensitive to radiations identifying the irradiated ones. 17.15.6 The total radiation dose must be applied for a pre-established period of time. 17.16 Sterilization by ethylene oxide

17.16.1 The sterilization method using the ethylene oxide must only be used when any other method is viable. During the process validation, it must be shown that there are no hazardous effects for the product and that the ventilation time is enough for the reactive gas and products wastes are below the limit established as acceptable for the product. 17.16.2 It is essential the direct contact between the gas and the microbial cells. The nature and quantity of packaging materials may significantly affect the process. 17.16.3 Before being subjected to the gas action, the materials must reach and maintain the balance with the temperature and humidity required by the process. The time used in this process must be considered to minimize the time before sterilization. 17.16.4 Each sterilization run must be monitored with appropriate biological indicators, an appropriate number of them must be used, distributed over all the load. The information obtained must be part of the batch documentation. 17.16.5 The biological indicators must be preserved and used according to the manufacturer’s instructions and their performance must be checked through positive controls. 17.16.6 For each sterilization run, a record of the sterilization running time, pressure, temperature and humidity inside the chamber during the process and the gas concentration must be kept. The pressure and temperature must be registered on a graphic during the run. The records must be part of the batch documentation. 17.16.7 After sterilization, the load must be stored in a controlled way, under ventilation conditions, so the presence of gas waste and reactive products decreases to acceptable levels. This process must be validated. 17.17 Filtration of drugs which may not be sterilized in their final containers 17.17.1 Whenever possible, the products must be sterilized in the final containers, specially by humid heat sterilization. Some solutions and liquids which may not be sterilized in their final containers, may be filtered to previously sterilized containers, through sterile filters, with 0.22 µm (or less) sized pores or presenting similar properties, to the retention of microorganisms. The possibility of supplementing the filtration process with some heating phases must be considered. 17.17.2 Filters which loose fibers must not be used. The use of amianthus filters must be definitely excluded. 17.17.3 The filter integrity must be checked though an appropriate method (e.g., application of the “bubble point” essay), before its use and immediately after its use. The time spent to filter a known volume of a certain solution and the difference of pressure used must be determined during the process validation. Any significant differences related to established standards must be recorded and investigated. The results of these verifications must be written in the batch documentation. 17.17.4 The filter must not affect the product, removing its active ingredients or adding other substances. 17.18 Finalization of the manufacturing steps 17.18.1 The containers must be sealed upon appropriate, duly validated procedures. Samples must be controlled in relation to their integrity, according to established procedures. In case of air-tightened closed containers, the samples must be controlled to check the air-tightness maintenance according to the pre-established period of time. 17.18.2 The final container containing parenteral products must be individually inspected. If the inspection is visual, it must be done under appropriate and controlled conditions of light and contrast. The operators designated to this job must be subjected to periodical exams of visual accuracy, considering the corrective lenses, if applicable, and frequent rest stops during the work shift. If other inspection methods are used, the process must be validated and the equipment trustfulness must be periodically verified. 17.19 Quality control 17.19.1 The samples collected to the sterility essay must be representative of the whole batch, an special attention must be given in the batch parts representing a higher contamination risk, such as:

(a) products that went through an aseptic filling process - the samples must include the initial and final containers of the batch, and also after any significant interruption of work; (b) products sterilized by heat in their final package - the samples must include the packages of the potentially colder areas of the load. 17.19.2 The sterility essay applied to the final product must be considered as the last one of a series of control measures, through which the sterility is guaranteed. The result of the essay can only be interpreted together with the records on the environmental conditions and the records related to the batch manufacturing. 17.19.3 The batches non-approved in the initial sterility test cannot be approved based on a second test, except if an investigation is performed on the kind of microorganism found and the records on the environmental conditions and on the batches processing, and the result of this investigation shows that the initial test was not valid. 17.19.4 In case of injectable products, the presence of endotoxins in the water used must be controlled, in the intermediary and finished products, using a pharmacopoeia method validated for each type of product. 18. Biological products 18.1 Reach 18.1.1 The purpose of this chapter is to supplement the “Good Manufacturing Practices for the Manufacturing of drugs”, reinforcing the specific points on the manufacturing of microbiological products. 18.1.2 The regulatory procedures requires to the control of biological products are, in a great part, determined by the products origin and by the manufacturing technology used. The manufacturing procedures in this Regulation include: growth of strains of microorganisms and eucaryotic cells; extraction of active principles from biological fluids or animal or vegetal (allergenic) tissues; recombining DNA technique (rDNA); hybridome technique; multiplication of microorganisms in embryos or animal organs. 18.1.3 The biological product manufactured with these technologies include antigens, vaccines, hormones, cytokines, enzymes, human plasma derivatives, hyperimmune serum (heterologue), biotechnology products and monoclonal antibodies. 18.2 Glossary The definitions presented below apply to the terms used in this Regulation, and they may show different meanings, in other contexts. Clean area Area with environmental control defined in terms of contamination by viable or non-viable particles, designed, built and used in a way to reduce the introduction, generation and retention of contaminants inside it. Manufacturing Cells Bank (MCB) Vials containing cells, obtained from a Seed Cell vial, preserved at temperature of <-70o C, used for the production of Cell Growth. Seed Cell Vials containing animal cells, from known origin, preserved at temperature <-70o C. Individual collection Suspension of microorganisms obtained from a Production Inoculums inoculated and colleted in a single production cycle. Production Cell Growth Suspension of cells, obtained from one or more vials from the Manufacturing Cells Bank inoculated and collected in a single production cycle. Production Inoculums Suspension of microorganisms, of uniform composition, obtained from one or more vials from the Secondary Batch.

Seed Batch Vials containing preserved microorganisms, or uniform compositions, obtained from a preserved strain and known origin. Secondary Batch (Work) Vials containing preserved microorganisms, of uniform composition, obtained from a Seed batch. Batch Registration Collection of documents related to the manufacturing of a certain batch of finished product. These documents describe the production procedures and record the operations related to the batch quality, including the Certificate of Batch Release. 18.3 General considerations 18.3.1 The manufacturing of biological products must be done according to the basic principles of the Good Manufacturing Practices (GMP). Therefore, the matters addressed in this chapter are not considered supplementary to the general rules established in the “Good Manufacturing Practices of Drugs” and are specifically related to the production and quality control of biological drugs. 18.3.2 The way the biological products are produced, inspected and administered make some special precautions necessary. On the contrary of the chemically defined drugs, which are usually manufactured and controlled by chemical and physical reproducible techniques, the biological products are manufactured with technologies involving processes and biological materials not always reproducible. 18.3.3 The production processes of biological products have an inner variability and therefore, the degradation and nature of the byproducts are not constant. For this reason, in the manufacturing of biological products it is even more critical that the recommendations established by GMPs are met, during all the production phases. 18.3.4 The quality control of the biological products almost always imply in the use of biological techniques with a larger variability than the physical-chemical determinations. The control during the process acquires a great importance in the production of the biological products because some quality deviations are not detected in the quality control essays performed in the finished product. 18.3.5 This Regulation does not establish detailed rules for specific classes of biological products and, therefore, the pertinent orientation in the Rules of Production and Quality Control specific to each product must be considered, when applicable. 18.4 Personnel 18.4.1 The manufacturing of biological drugs must be oriented by a person expert in the manufacturing techniques and who knows the scientific principles upon which these techniques are based. The staff must include experts with specific graduation for the products produced in the premises. 18.4.2 The personnel working in the clean areas must be carefully selected, in order to ensure the fulfillment of the requirements of the Good Manufacturing Practices. The employees selected must not present any health disorder which might compromise the product integrity. 18.4.3 The personnel must rigorously follow the cleaning and personal hygiene procedures. 18.4.4 The personnel must be oriented to inform any health disorder (diarrhea, cough, cold, contaminated skin, wounds, fever of unknown cause) which may cause microorganisms contamination in the working environment, different to the ones used in the production. 18.4.5 Admission and periodical medical examinations must be performed in the staff to detect any health disorder. 18.4.6 All the health condition change which might affect the product quality implies in the exclusion of the person from the production areas. 18.4.7 When working in clean areas, only the minimum personnel required must be present. Whenever possible, the inspection and control procedures must be performed from outside of these areas. 18.4.8 During the working shift, the personnel must not pass from the areas where they manipulate microorganisms or live animals to the premises where other products or organisms

are being worked with, unless the definite decontamination measures are applies, including the change of uniform and shoes. 18.4.9 Person non-authorized must not enter into the production areas, unless for specific purposes and, at last instance, they must be wearing appropriate and sterilized garments. 18.4.10 The designees for production must be different from the personnel responsible for the animal care. 18.4.11 In order to ensure the quality of the manufactured products, personnel must be trained in the Good Manufacturing Practices and have graduation and knowledge of the specific areas, according to the product manufactured. 18.4.12 There must be records of the trainings. The training programs must be evaluated to proved their efficacy. 18.4.13 All personnel directly or indirectly involved in the production must be immunized with specific vaccines and, when required, subjected to periodic tests to the detection of infectious-contagious diseases signs. 18.4.14 When BCG vaccine is manufactured, the access to the production areas must be restrict to personnel carefully monitored through periodical medical examinations. 18.4.15 In case of the manufacturing of blood or human plasma derivatives, personnel must be immunized with the vaccine for hepatitis B. 18.5 Premises and Equipment 18.5.1 As general principle, the premises must be located, designed, built, adapted and preserved to be appropriate to the operations performed there. The areas used in the production, the quality control laboratories and all the other areas (including the ones designed to animals used in the manufacturing of biological products) must be designed to gather the best hygiene conditions and protection against dust, insects and rodents, and they must be built with materials appropriate to the purpose they are designed for. 18.5.2 The internal surfaces (walls, floor and ceiling) must be plain with no cracks; they must not loose material and must be easy to clean and disinfect. 18.5.3 Drains must be avoided in the production areas to eliminate wastes, unless required and, when there are drains, they must have siphons easy to clean and disinfect, with valves avoiding counter-flow. 18.5.4 There must not be drains in the clean areas. 18.5.5 If there are external pipes for draining, in the floor, it must be open, plain, easy to clean, and it must be connected to drainage, to avoid the entrance of contaminants in the area. 18.5.6 Lavatories must not be installed in the clean areas of classes A, B and C. The lavatories installed in other clean areas must be made of materials easy to clean, such as stainless steel. 18.5.7 Special cares must be taken to avoid contamination of the wastes elimination system, with dangerous effluents. 18.5.8 The air dissemination of pathogen microorganisms handled in the production must be avoided. 18.5.9 The product contamination by other microorganisms and substances, including the ones from the personnel involved in the production process, must be avoided. 18.5.10 The illumination, heating, ventilation and, when required, the air conditioning system must be designed to maintain the temperature and relative humidity of the air in the appropriate conditions for each product; reduce the contamination to a minimum and it must also take into account the comfort of the personnel working with protecting garments. 18.5.11 The buildings must be in good preservation conditions and must be regularly inspected to identify the need of repairs. 18.5.12 Special care must be taken to ensure that the repair or maintenance operations of buildings do not affect the products. 18.5.13 The premises must provide space enough for the operations to be performed safely and to allow the continuity and efficiency of work. 18.5.14 All the buildings and other areas must be in satisfactory cleaning and hygiene conditions full time. 18.5.15 The areas used to work with animal tissues and microorganisms not used in the production process, as well as, where the animals or microorganism essays are performed,

must be separated from the premises used in the production of sterile biological products, with independent ventilation and different staff. 18.5.16 In the areas used for the production of products in campaign, the premises design and placement of equipment must allow a rigorous cleaning and sanitization after production and, when required, the efficient decontamination through sterilization and/or fumigation. All the processes used must be validated. 18.5.17 The seed batch and the cell bank, used in the manufacturing of biological products must be stored separated from the other materials. The access to these materials must be restrict to authorized persons only. 18.5.18 The live microorganisms must be handled in equipment and with procedures ensuring the maintenance of the cultures purity, as well as, protecting the operator from contamination with the microorganism mentioned. 18.5.19 Biological products, such as vaccines with dead microorganisms, toxoids, extracts from bacteria, including the ones prepared through the recombinant DNA technique, may, once inactivated, be filled in the same premises used for other sterile biological products, provided that appropriate measures of decontamination after filling are taken, including cleaning and sterilization. All the processes used must be validated. 18.5.20 Biological products from sporulated microorganisms must be handled in exclusive premises for this group of products, until the inactivation process is finished. When dealing with Bacillus anthracis, Clostridium botulinum and Clostridium tetani, isolated and exclusively designed premises must be used for each one of these products. 18.5.21 When in a premise or group of premises preparations of sporulated microorganisms for the production in campaign are performed, only one product must be produced at a time. 18.5.22 The manufacturing of products derived from human blood or plasma, premises and equipment designed exclusively for this purpose must be done. 18.5.23 All the containers with biological substances, of any production step, must be identified with firmly adhered tags. 18.5.24 The cross-contamination must be avoided adopting any one of the following measures or all of them: 18.5.24.1 to perform the production and filling in specific areas; 18.5.24.2 to avoid the production of different products at the same time; unless they are effectively in physically separated areas; 18.5.24.3 to transfer biological materials safely; 18.5.24.4 to change garments when entering different production areas; 18.5.24.5 to clean and decontaminate carefully the equipment; 18.5.24.6 to take precautions against the contamination risks caused by recirculation of air in the clean environment or by the accidental return of the disposed air; 18.5.24.7 to use “closed systems” in the production; 18.5.24.8 to avoid the formation of aerosols (mainly by centrifugation and mixings); 18.5.24.9 to prohibit the entry of pathological samples in the areas used for the production of biological substances; 18.5.24.10 to use sterilized containers, and when requires, depyrogenized containers. 18.5.25 The preparation of sterile products must be performed in clean area with positive air pressure. But, all the organisms considered as pathogens must be handled with negative air pressure, in places specially separated for this purpose, according to the isolation rules for these products. 18.5.26 The areas where pathogen microorganisms are handled must have an exclusive system of air circulation. The air must be disposed through sterilizing filters which functioning and efficiency must be periodically checked. The filters used must be incinerated after disposal. 18.5.27 When used in the production of pathogen microorganism products, the production area must have specific decontamination systems of effluents.

18.5.28 The ventilation pipes, valves and filters of the equipment must be designed to make their cleaning and sterilization easier. The fermentation container valves must be sterilizable and appropriate to use. 18.5.29 Small amounts of substances to be used during the production process may be left in the production areas, provided that they are not returned to warehouse. 18.5.30 The powdered raw material, used in the preparation of means of culture, buffers, etc., must be handled outside the clean areas and purification areas, viewing the minimum contamination of the product with particles. 18.6 Production 18.6.1 In all manufacturing operations the duly updated Standard Operation Procedures (SOP) must be followed. 18.6.2 The specifications of raw materials must include details, such as manufacturer, origin, production process and quality control analyses performed. The release of the raw material to be used in the production is conditioned to its previous approval by the company’s quality control. 18.6.3 The mean of culture must be added to the fermentation tank or to another container under controlled conditions to avoid contamination. Care must be taken in order to endure that the containers are correctly connected during the transfer of the mean of culture. 18.6.4 When possible, the means of culture must be sterilized in situ. 18.6.5 When possible, sterile filters installed and sterilized in-line must be used to add gas, means of culture, acids, alkalis, anti-foaming agents, etc., to the fermentation containers. 18.6.6 The sterilization process must be validated. 18.6.7 When an inactivation process is performed during the production, measures must be taken in order to avoid the risk of cross-contamination between the active and inactive products. 18.6.8 The chromatography column used in the production of biological products, must be designed to the purification of only one product, and it must be sterilized or sanitized after each process run. The shelf-life of the resin used and the method of sterilization and/or sanitization used must be defined. The maximum limits of microbial load and endotoxins in the column must be established. 18.6.9 In the production of Hemoderivatives, human plasma used as raw material must originate from whole blood units and/or plasmapheresis individually subjected to the binding serological control established by the National Rules. Each plasma unit tested must be non-reagent to the serological controls performed. 18.7 Labeling 18.7.1 All the products must be clearly identified. The labels used must maintain well adhered to he containers, no matter the storage conditions. If the definite filling container does not allow to place a label, it must be placed in a labeled package. 18.8 Batch records 18.8.1 The batch records must provide the complete data of the background of the manufacturing of each batch and show that they were produced, filled, and controlled according to the approved procedures 18.8.2 There must be a production order for each batch size, that is the faithful copy of the master/standard formula. 18.8.3 All the data required to the following of the different steps of the production process and quality control tests of each batch must be recorded. 18.8.4 The record of each product batch must be kept by the manufacturer for, at least, two years after the batch expiration date. 18.9 Quality assurance 18.9.1 The Quality Assurance and/or the Quality Control have, but are not limited to, the following responsibilities: 18.9.1.1 To approve the Standard Operation Procedures (SOPs) for each production process and quality control; 18.9.1.2 to ensure that the samples used in the tests are identified and packaged in a way to maintain their integrity;

18.9.1.3 to ensure that constant managements of the environmental conditions are performed; 18.9.1.4 to ensure the perfect functioning of the equipment and instruments used in the production steps and quality control; 18.9.1.5 to evaluate and approve raw materials, packaging materials, intermediary products, bulk products and finished products; 18.9.1.6 to ensure the appropriate storage conditions of raw materials, intermediary and finished products; 18.9.1.7 to determine the stability of the finished products and, when required, of the raw materials, intermediary products and bulk products. 18.9.1.8 to establish the expiration date for each product as for the specific stability conditions; 18.9.1.9 to establish the specifications of materials, the production and quality control procedures and the date for revision; 18.10 Quality control 18.10.1 The Quality Control must be independent from the production. 18.10.2 The Quality Control must have the area and equipment required and sufficient to operate as a complete unit with proper areas to file documents, keep reference samples and perform quality control tests. 18.10.3 The quality control essays which may not be performed in the finished product, must be performed in a defined step of the production. 18.10.4 Some production steps must be monitored and registered continuously, by the quality control, during all the production process. 18.10.5 It must be taken special care in the quality control procedures when using continuous cell lines to obtain a biological product. 18.11 Animals premises 18.11.1 The animals used in the production and quality control must be placed in premises independent from the other areas of the company, with independent ventilation systems. 18.11.2 The design of the premises and the construction materials used must allow the maintenance of the areas in hygiene conditions and have counter-entrance for insects and other animals. 18.11.3 The personnel working with the animals must wear garments for exclusive use in the area. 18.11.4 The premises to animal care must include an isolation area to quarantine animals entering and an area to store food. 18.11.5 The animals inoculation area must be distinct from the one designed to the performance of necropsy. 18.11.6 There must be a premise to disinfect cages, if possible, to sterilize them with steam. 18.11.7 It is required to control and record the health condition of the animals used. 18.11.8 Special precautions are required when using monkeys in the production or quality control. 18.11.9 The wastes and corpses of animals must be eliminated with safety, decontaminated by sterilization and, if possible, incinerated. 19. Validation of the Manufacturing Processes 19.1 Reach 19.1.1 The purpose of this chapter is to establish the principles and concepts of the validation procedures to supplement the “Good Manufacturing Practices of Drugs”, reinforcing the specific points on validation of manufacturing processes of drugs. 19.1.2 Validation is a documented act attesting that any procedure, process, equipment, material, operation, or system really conduct to the expected results. 19.1.3 The validation of processes is an additional requirement to the “Good Manufacturing Practices of Drugs”, therefore, it has a general application to all drugs. 19.1.4 Any procedure different from the described general procedures in this chapter is not recognized, unless, its validity is shown.

19.1.5 The fulfillment of the “Good Manufacturing Practices of Drugs” require the validation of the production processes, as well as the validation of any change introduced in the production processes, which might affect the quality of the product. 19.1.6 The validation of all the manufacturing processes and support activities must be performed, including the cleaning operations. 19.1.7 The validation of the analytical procedures has the purpose of showing that the essay methods used present results allowing the objective evaluation of the quality of the drugs, according to the specified parameters. Each new analytical procedure must be validated. 19.1.7 The equipment, instruments and glassworks used in the analytical essays must be qualified and/or certified. The measuring instruments used for this qualification, must be calibrated. 19.2 - Glossary The definitions presented below apply to the terms used in this Regulation. The same terms may present different meanings, on another context. Calibration Group of operations establishing, under specified conditions, the relation between the values shown by a measuring instrument, system or values presented by a measuring material compared to the ones obtained with a correspondent reference standard. Acceptance criterion Criterion establishing the acceptance limits of the specifications of raw materials, products or processes/systems, required to take the decision of accepting or not, related to a certain sampling plan, when applicable. Specifications Document describing in details the requirements the products or materials used or obtained during the manufacturing must meet. The specifications act as the base for the quality evaluation. Validation Master Plan (VMP) Planning of all the validation activities with the purposes, procedures, deadlines and responsibilities defined. Production Process Production of drugs from defined raw materials, in a single process or in a sequence of processes, involving premises, personnel, documentation, and environment. Validation Protocol Company document specific for each activity describing the procedures to be performed in the validation, including the acceptance criteria for approval of a production process or part of it. Equipment qualification (EQ) Collection of operations establishing, under specified conditions, that the results of the tests of a certain equipment show that it presents the expected performance. The measuring instruments and systems must be calibrated. Installations qualification (IQ) Collection of operations establishing, under specified conditions, that the installation of equipment, utilities, weighing and measuring instruments and production areas, in the drug manufacturing, were properly selected and are correctly installed, according to established specifications. Operational qualification (OQ) Collection of operations establishing, under specified conditions, that the system or sub-system presents the expected performance, in all operational bands considered. All the equipment used to perform the tests, must be identified and calibrated before their use. Validation report Document where the records, results and evaluation of a finished validation process or system are gathered.

Revalidation Repetition of the approved validation process, that provides the guarantee that the changes introduced in the process/equipment, according to the changes of procedures or periodical repetition performed at scheduled periods, do not adversely affect the characteristics of the process neither the product quality. Choice tests/ worst case A condition or collection of conditions comprehending the higher and lower limits of processing and the respective circumstances, within the specifications of the Standard Operation Procedures, presenting the higher possibilities of product or process defect, when compared to the ideal conditions. Validation Documented act attesting that any procedure, process, equipment, material, operation or system, really conduct to the expected results. 19.3 - General considerations 19.3.1 The validation is part of the Quality Assurance. The validation involves the systematic study of the premises, systems, and processes with the purpose of determining if they perform their function properly and consistently, according to the specified. A validated operation ensured the production of uniform batches which meet the required specifications. 19.3.2 On the contrary of many GMP requirements, validation by its own does not improve the processes. It may only confirm or not, depending on the case, that the process was properly developed and the it is under control. 19.3.3 All the activities of product developing must be concluded with a validation phase, this includes, specially, the manufacturing of products under clinical trial and when the large scale production of products developed in pilot designs is started. 19.3.4 The validations performed during the development phase of the products do not guarantee that all production processes are properly validated. Consequently, validation must be discussed within a broader context, as an activity started during the development and that continues until the large scale production. 19.3.5 The validation processes required the mutual collaboration of all sectors involved, such as development, production, engineering, maintenance, quality assurance and quality control. 19.3.5 Validation allows: 19.3.5.1 To enhance the knowledge in the production processes and, thus, to ensure that the processes are under control. 19.3.5.2 To decrease the risks of quality deviation. 19.3.5.3 To decrease the risks of the non-conformity to the established requirements. 19.3.5.4 To decrease the quantity of quality control tests in the in-process control steps and in the finished product. 19.4 Types of process validation 19.4.1 Prospective validation The prospective validation is a documented act, based in the execution of a previously defined tests plan, showing that the new system, process, equipment or instrument, not in operation yet, meets the functional specifications and performance expectations. 19.4.1.1 The prospective validation is performed during the product development step, through the analysis of the risk of the manufacturing process, which is detailed in individual steps; these steps, by their turn, are defined based on the previous experience to determine if they can cause critical situations. 19.4.1.2 The critical points must be identified, evaluated as for their probability and extension, and have their causes researched. The research plans are defined, establishing the priorities and their final evaluation. 19.4.1.3 If, at the end of the validation process, the results are acceptable, the process is satisfactory. If the results are unsatisfactory changes in the process must be searched until it presents acceptable results. This validation form is essential to limit the risk of errors occurring in the large scale production. 19.4.2 Concurrent or simultaneous validation

The concurrent validation is performed during the routine production. This method is only efficient if the product development step resulted in the appropriate knowledge of the process basis. The first batches of the industrial production must be monitored as broadly as possible. The nature and specifications of the subsequent in-process tests and final tests are based in the evaluation of the results of the mentioned management. 19.4.2.1 The concurrent validation, together with a analysis of trend including the stability studies, must be performed with the appropriate extension along the product life. 19.4.3 Retrospective validation Retrospective validation is a documented act, based on the revision and analysis of the background records, attesting that a system, process, equipment or instrument, already being used, meets the functional specifications and performance expectations. 19.4.3.1 The retrospective validation involves the verification of the past experience of production, assuming that the composition, procedures and equipment keep unchanged; the mentioned experience and the results of the in-process control and final control tests are evaluated. The difficulties and defects registered in the production are analyzed to determine the limits of the process parameters. A trend analysis may be performed to determine the extension in which the process parameters are within the allowable range. 19.4.3.2 Obviously, the retrospective qualification is not, in itself, a guarantee measure of quality, and it must never be applied to new processes or products. It can only be considered in special circumstances, e.g., when the validation requirements are established for the first time within the company. In this case the retrospective validation may be useful to establish the priorities in the validation program. If the retrospective validation results are positive, this indicates that the process does not require immediate attention and may be validated according to the normal schedule. 19.4.4 Revalidation The revalidation is required to ensure that the intentional or non-intentional changes in the production process, equipment and environment, do not adversely affect the process characteristics and the product quality. The revalidation may be divided into two broad categories: 19.4.4.1 - Revalidation after any change may alter the product quality. 19.4.4.1.1 The revalidation must be performed when any changes which might affect the manufacturing and/or standard procedure, influencing the performance characteristics established for the product are introduced. 19.4.4.1.2 Each raw material, packaging material, manufacturing process, equipment, in-process controls, manufacturing areas and utilities (water, steam, etc), must be evaluated by the company validation group, which decides if it is significant enough to justify a revalidation and, its extension. 19.4.4.1.3 The revalidation after the changes may be based on the performance of the same tests and activities performed during the original validation, including the in-process tests and the ones related to the equipment. Some typical changes requiring revalidation are: Raw material: changes in the physical properties, such as density, viscosity, granulometry and type of crystal, which might adversely affect the process or product. Packaging material: any packaging procedure change which might affect the product stability, e.g., replacement of a plastic material for filling for a glass material. Process: any change which might affect the subsequent steps of the process and the product quality, e.g., mixing time, drying temperature and cooling procedure. Equipment, including measuring instruments: any replacement, repair and maintenance which might affect the process as well as the product; In the production area and utilities: any replacement, repair and maintenance which might affect the process as well as the product, e.g., repair and maintenance of the ventilation system might change the environmental conditions and, consequently, its revalidation might be required, specially in the manufacturing of sterile products. When deviations are detected during the self-inspection or audit, or during the continuous analysis of the process data trend.

19.4.4.2 Periodic revalidation: The changes of process might occur gradually, even when experimented operators work correctly, according to the established methods. Similarly, the excessive use of the equipment might also cause gradual changes. The revalidation into scheduled periods is recommended, including cases where no change is detected, considering the use of the equipment and possible human errors. 19.4.4.2.1 The decision of implementing periodical revalidation must be based specially on the background data revision, generated during the in-process tests and finished product tests, after the last validation, with the purpose of checking if the process is under control. During the revision of the background data mentioned, any bias of the collected data must be evaluated. 19.4.4.2.2 In some production processes, the following points must be checked in the revalidation: 19.4.4.2.2.1 If there is any change in the formula, procedures, batch size, etc. If positive, if its impact on the product was evaluated. 19.4.4.2.2.2 If the calibrations were performed according to a established schedule. 19.4.4.2.2.3 If the prevention maintenance was performed according to a established schedule. 19.4.4.2.2.4 If the Standard Operation Procedures (SOPs) were properly updated. 19.4.4.2.2.5 If the SOPs were implemented. 19.4.4.2.2.6 If hygiene and cleaning program were implemented. 19.4.4.2.2.7 If any change on the control analytical methods was performed. 19.5 Pre-requisites to the validation of a production process. 19.5.1 Before starting the process validation, the equipment used in the production and the control instruments, as well as the formulation must be qualified. The drug formulation must be studied in detail and qualified in the development step. This involved the pre-formulation studies, studies on the compatibility of active principles and excipients, as well as the finished product and the packaging material, stability studies, etc. 19.5.2 Other aspects on the production must be validated, including the utilities (water, air, nitrogen, electrical power, etc.) besides the support operations, such as cleaning and sanitization of equipment and premises. The appropriate training and motivation of personnel are pre-requisite to a successful validation. 19.6 Approaches 19.6 There are two basic approaches to the process validation: 19.6.1 Experimental approach, which is applicable to the prospective and concurrent validations: 19.6.1.1 Broad product test. 19.6.1.1 One of the most practical process validation, specially to non-sterile products, is the final product test with a larger extension than the required by the routine quality control. It may involve the broad sampling, much beyond the one used to the routine quality control and tests according to the normal quality control specifications, and usually only for some parameters. Thus, for instance, some hundreds of tablets may be weighed by batch to determine the dose uniformity. Then, the results are statistically treated in order to check the distribution normality and to determine the average weight standard deviation. The trust limits to individual results and to the batch homogeneity are also estimated. A broad safety that the samples randomly collected meet the requirements of the regulation is provided if the trust limits are met within the compendia specifications. 19.6.1.1.2 Similarly, sampling and broadening tests may be performed in relation to any quality requirement. Additionally, the intermediary steps may be validated the same way, samples may be individually essayed to validate the mixing steps or granulation steps in the low dose tablets production, using the content uniformity test. The non-visible particle, in parenteral preparations, may be detected through electronic devices. 19.6.1.2 Process conditions simulation 19.6.1.2.1 The process simulation characteristics are mainly used to validate the aseptic filling of parenteral products which may not be sterilized in their final presentation. This involves the vials or

vial-flasks with mean of culture under normal conditions, followed by the incubation and control of microbial growth, the number of vials and vial-flasks contaminated must be less than 0.1%. 19.6.1.3 Choice conditions / worst case 19.6.1.3.1 The procedure choice to be validated must have as a priority the activities related to the process capacity, e.g., the process capacity may operate with no difficulties when the parameters are close to acceptable limits. The use of acceptance bands to the raw material quality in experimental batches may make the estimation of the extension where the process is still able to produce a final product meeting the specifications possible. 19.6.1.4 Process parameters control 19.6.1.4.1 The physical parameters of the process are monitored in normal production runs in order to obtain additional information on the process and its trust. Additional devices sensitive to temperature, installed in an autoclave or in a sterilization/depirogenization heater, allow to perform a detailed study on the distribution of the heat to the many loads. Heat penetration measures must be performed to the products for injection presenting a higher viscosity or volumes above 5 mL. The equipment for compression and production of tablets equipped with cells sensitive to pressure is useful to the collection of statistical data on the compression uniformity and, therefore, on the weight uniformity. 19.6.2 Approach based on the background data analysis 19.6.2.1 In the approach based on the background data analysis retrospective validation experiments are not performed, but, on the contrary, all the background data available related to a number of batches are combined and analyzed together. If the production is being developed with no difficulties during the period previous to the validation, the in-process tests data and the product final tests must be statistically collected and evaluated. The results, including the process capacity studies, bias analysis, etc., indicate whether the process is under control or not. 19.6.2.2 The results and quality control and process records may be used, to the retrospective validation. A careful revision of the graphics allows to estimate the process trust. A process can be considered trustful if the data recorded are within the control limits and the individual results range are stable. 19.6.2.3 Additionally, the information on the problems related to the product is also analyzed. The process trustful is shown if, during a considerable time, there are no rejections, complaints, returns, unexpected adverse reactions, etc. The process may be certified as retrospectively validated if the statistical analysis results are satisfactory, and the absence of quality deviation is documented. But, it must be emphasized that this approach is not applicable to the manufacturing of sterile products. 19.6.3 Example of priorities to a production process validation program Table 1 Type of process Validation requirements New Process

All new processes must be validated before their approval for routine production.

Routine process to the production of sterile products

All the processes affecting the sterility and the environment of the manufacturing must be validated; specially the sterilization process.

Routine production for the production of Non-Sterile products

Low dose tablets and capsules containing highly active substances: mixing validation and granulation related to the content uniformity. Other tablets and capsules: validation of the operation of tablets compression and capsules filling related to the weight uniformity.

19.6.4 It may be noticed that, once prepared the previous batches control graphics, they become a potent tool to the prospective quality management. The data to new batches are recorded over the same graphics, and, for each result out the control limits, a reason for this deviation is searched and once found, it must be eliminated. Applying this approach, consistently during a certain period of time, the process may be considered satisfactory. 19.7 Organization 19.7.1 In the Organization chart of the company the responsibilities to the validation activities must be established. For this purpose, the company Board, must designate a person responsible for the validation activities (head of validation), who institutes a validation group (team, committee). This group must have representatives of all the main sectors: Development, Production, Engineering, Maintenance, Quality Assurance and Quality Control. The group composition must be periodically renewed, in order to propitiate the opportunity for other people to contribute with new ideas and to acquire experience. The group prepares a validation program defining its priorities, schedule, required resources, etc. A program must be revised and approved by the sectors involved. The final revision and approval are a responsibility of the head of validation. 19.8 Scope of a process validation program The priorities suggested for a validation program are related in Table 1. For new processes it is recommended that the first three (3) industrial production batches are not released from quarantine after their approval by the quality control, until their validation is concluded, the results presented and revised and the process approved. 19.9 Validation Master Plan The Validation Master Plan of a specific process, must contain, at least, the following topics: 1. Purpose (and previous requirements) 2. Presentation of the whole process and sub-processes, flow chart, critical points / risks 3. Organization structure of the validation activities 4. Reason for inclusion or exclusion from a certain validation 5. Tracking system for reference and revisions 6. Required trainings for a validation program 7. Type of validation defined for each system or project 8. Planning and chronogram of the activities to be performed 9. Cross-reference and other documents The Validation Master Plan must include the cleaning procedures and analytical methods validation.

ANNEX II Evaluation Classification and Criteria to the items in the Inspection Guide to Companies Manufacturing Drugs. The criterion established for the classification is based in the potential risk inner to each item in relation to the quality and safety of the product and worker safety in his/her interaction with the products and processes during manufacturing. INDISPENSABLE - I The item considered INDISPENSABLE is the one that meets the Good Manufacturing Practices recommendations, which might influence in a critical level the quality or safety of the products and the safety of the workers in their interaction with the products and processes during the manufacturing. Defined by YES or NO

NECESSARY - N The item considered NECESSARY is the one that meets the Good Manufacturing Practices recommendations, which might influence in a less critical level the quality or safety of the products and the safety of the workers in their interaction with the products and processes during manufacturing. Defined as YES or NO The item NECESSARY not met in an inspection, will be consequently classified as INDISPENSABLE in the following inspections. RECOMMENDABLE - R It is considered RECOMMENDABLE the item which meets the recommendations of Good Manufacturing Practices which might influence in a non-critical level the quality or safety of the products and the safety of workers in their interaction with the products and processes during the manufacturing. Defined as YES or NO The RECOMMENDABLE item not met in an inspection, will be consequently classified as NECESSARY in the following inspections. However, it will never be considered INDISPENSABLE. INFORMATIVE - INF The item considered INFORMATIVE is the one that presents a descriptive information, which does not affect the quality and safety of the products and the safety of the workers in their interaction with the products and processes during the manufacturing. It may be answered optionally as YES or NO, or descriptively.

ANNEX III Inspection Guide to Companies Manufacturing Drugs

1.- MANAGEMENT AND GENERAL INFORMATION The company must present the proving documents required.

No. Qualif. Items YES NO N/A 1.1 INF Name of the Company?______________________________ 1.1.1 INF CNPJ [National Directory of Legal Entities]:_______________________

1.1.2 INF

Address Street/Ave: _____________________________________________ No._______________, Complement: __________________________ Neighborhood ___________________ Municipality: ________________ State: _______________ CEP [ZIP CODE]:_______________ Telephone: ___________________________________ Fax: __________________________________________ E-mail: ________________________________________

1.2 INF Inspection period ___/___/___ to ___/___/___ 1.2.1 INF Reason for inspection _________________________________ 1.3 INF Date of last inspection: ___/___/___ 1.3.1 INF Reason for the last inspection: ___________________________

1.4 INF Does it have a Good Manufacturing Practice Certificate?

1.4.1 INF Date of issue of the certificate ___/___/___ 1.5 INF Name of the Technical Responsible ________________________________ 1.6 I Is the responsible pharmaceutical present?

1.7 I Is there a proof of his/her inscription in the competent authority?

1.8 N Did the company present any organization chart?

1.9 I

Does the company have a Certificate of Establishment granted by the competent Authority of the National Sanitary Surveillance System?

1.9.1 INF Number _______________________________________________

1.9.2 INF Authorized activities:

Store Package Distribute Export Import Manufacture Produce Transport Repackage Extract Issue Fractionate Synthesize Transform Purify

1.10 I

Does the company have a Special Certificate of Establishment granted by the competent Authority of the National Sanitary Surveillance System?

1.10.1 INF Number: _______________________________________________

1.10.2 INF Authorized activities:

Store Package Distribute Export Import Manufacture Produce Transport Repackage Extract Issue Fractionate Synthesize Transform Purify Manipulate

1.11 I The entries and balance of substances subject to the special control regimen are done following the current Sanitary Legislation?

1.12 I Are the losses from the manufacturing processes of manufacturing of products subject to the special control regimen duly entry?

1.13 I Does the company have a Certificate of Establishment / Sanitary Authorization from the local Authority?

1.13.1 INF Number: ______________________________________________ 1.14 Does the company have authorization from the competent Authorities for: 1.14.1 N Environmental protection? 1.14.2 N Premises safety (fireman)?

1.14.3 N

Does the company responsible for transportation of raw materials and/or finished product have a certificate of establishment for this activity before the competent Sanitary Authorization?

1.15 N Were the building plans presented? 1.15.1 INF Which is the terrain surface? ____________________ m2 1.15.2 INF Which is the total built area? ____________________ m2 1.15.3 INF How many buildings does the plan have? ____________________________ 1.16 INF Is there a restaurant / cafeteria in the company?

1.17 N Is there an Occupational Health Program updated and duly signed by the responsible physician?

1.18 N Was a list of products of the company’s property presented, with the marketed and the non-marketed products?

1.18.1 I Are all these products duly registered in the competent National Sanitary Authority?

1.19 INF Which is the installed capacity of production of the company by line/pharmaceutical presentation? (Annex documentation)

1.20 R Was a ground plan updated and approved by the competent Sanitary Authority presented?

1.21 R Is the flow of personnel and materials indicated in the ground plan updated and approved by the competent Sanitary Authorization?

1.22 INF Does the company hires third party services to the production of its products?

1.22.1 INF What are the products and steps performed by third parties? ____________ _____________________________________________________________

1.22.2 INF Which are the hired companies? ____________________________________

1.22.3 N Were the contracts of third parties filed to evaluation of the competent Sanitary Authority?

1.22.4 INF Does the company hire services from third parties to the production of products subject to the special control regimen?

1.22.4.1 INF Which are the hired companies? ___________________________________

1.23 INF Does the company hire the services of third parties to the analysis of raw materials and/or products?

1.23.1 INF Which are the hired companies? ___________________________________ 1.23.2 N Which are the essays performed?

1.23.3 N Were the contracts for third parties to analyze raw materials and/or products filed to evaluation of the competent Sanitary Authority?

1.24 INF Does the company import raw material? 1.25 INF Does the company import intermediary products? 1.26 INF Does the company import bulk material? 1.27 INF Does the company import finished products?

1.28 R Did the company present a list of the imported products (intermediary, bulk, finished)?

1.29 INF Were the lines where the imported products are manufactured already certified by the competent Sanitary Authority in Brazil?

1.29.1 N If not, did the company request the inspection to the competent Sanitary Authority in Brazil yet?

1.30 INF Does the company export finished products?

1.30.1 R Did the company present a list of the exported finished products?

1.31 INF

Does the company perform activities related to the industrialization of products of different nature or purpose subject to the competent Sanitary Authority Authorization?

1.31.1 INF Specify the products. ___________________________________________

1.32 N Did the company produce three (3) pilot batches of registered product according to the current legislation?

1.32.1 INF What was the destination of these batches? 1.32.2 N Are there records? 2. -PREMISES 2.1- General conditions

No. Qualif. Items YES NO N/A

2.1.1 INF Are there environmental pollution or contamination sources next to the company?

2.1.2 R Are the access routes paved?

2.1.3 N Are the building surrounding areas clean?

2.1.4 R As for the external aspect, do the buildings show a good conservation (absence of cracks, infiltrations, etc.)

2.1.5 N Are the effluents treated?

2.1.5.1 INF What are the treatments used? ______________________________

2.1.5.2 N Are there records?

2.1.6 N Are the premises built in a way to allow the protection against the entrance of insects and other animals?

2.1.6.1 N Is there a prevention and fighting program to insects and other animals?

2.2. Auxiliary premises No. Qualif. Items YES NO N/A

2.2.1 Garments and Restrooms 2.2.1.1 R Are there enough locker rooms?

2.2.1.1.1 N Are they in appropriate hygiene conditions?

2.2.1.2 R Are there enough restrooms?

2.2.1.2.1 N

Are they in satisfactory hygiene conditions and provided with cold and/or hot water, soap and dischargeable towels or hand-driers?

2.2.1.2.2 N Is the access to the restrooms independent in the production areas and in the warehouse?

2.2.2 Maintenance/Utilities

2.2.2.1 INF Are the maintenance areas physically separated from the production areas?

2.2.2.2 INF Is there a specific area to the steam generator equipment?

2.2.2.2.1 INF Is industrial steam produced? 2.2.2.2.2 INF Is pure steam produced?

2.2.2.3 INF Is there an area to the compressed-air compressor equipment?

2.2.2.4 INF Is there a specific area to the equipment to produce purified water?

2.2.2.5 INF Is there a specific area to the equipment to produce water for injection?

2.2.2.6 INF Is there a specific area to the air-conditioning equipment?

2.2.2.7 INF Is there a capture center of post-wastes from the exhaustion system?

2.2.2.8 N Is there an electric power generator to emergency cases, if required?

2.2.2.9 N Are the water, steam, gas, compressed air, and electricity pipes duly identified?

2.2.3 Creation biotherium

2.2.3.1 N Are the creation biotherium premises independent from the other premises?

2.2.3.2 N Do all the activities performed in this area meet the previously defined SOPs?

2.2.3.2.1 N Are there records of the critical operations defined in the respective SOPs?

2.2.3.3 N Are the hygiene conditions appropriate?

2.2.3.4 N Are there separated restroom and locker room to the personnel working with animals?

2.2.3.4.1 N Are the hygiene conditions appropriate?

2.2.3.5 INF What are the animal species growth? ______________________

2.2.3.6 INF Is the animals origin known?

2.2.3.7 INF Is the creation area enough to accommodate the many animal species used?

2.2.3.8 N

Is the ventilation system and/or air conditioning system of the biotherium independent from the other installations of the company?

2.2.3.9 N Is the illumination enough? 2.2.3.10 N Is there a quarantine area to animals? 2.2.3.11 N Is there a room for inoculated animals?

2.2.3.12 N Is there a room for disinfection and drying of the boxes, cages, feeders, and other required materials?

2.2.3.13 N Is there an appropriate place to the storage of materials, food and beds of animals?

2.2.3.14 N Is the treatment of animals disposals and corpses established in the SOP?

2.2.3.14.1 N Is there an appropriate place to the animals disposals and corpses be stored?

2.2.3.15 N Is there a qualified professional responsible for the Biotherium?

3.- WAREHOUSES/ MATERIALS AND PRODUCTS 3.1.- General conditions

No. Qualif. Items YES NO N/A

3.1.1 N Are the floors, walls and ceilings appropriate to the activities developed in the area?

3.1.1.1 N Are they in a good conservation condition?

3.1.1.2 N Are they easy to clean?

3.1.1.3 N Are they clean?

3.1.2 N Is there protection against the entry of rodents, insects, birds and other animals?

3.1.2.1 N Is there a system to fight them?

3.1.2.2 INF Who is the person responsible for its execution? _____________________________

3.1.2.3 INF Was an incidence of the presence of rodents, insects, birds, or other animals shown?

3.1.4 R Is the illumination appropriate?

3.1.5 INF Is there the need to control humidity and temperature in the warehouses?

3.1.5.1 N If so, there are apparatus controlling the humidity and temperature?

3.1.5.2 N Are there records?

3.1.6 N

Are the temperature and humidity consistent with the established parameters for the materials and products stored?

3.1.6.1 N

In case of deviations related to the established parameters is an investigation done to evaluate the causes?

3.1.6.2 N Are preventive and/or corrective actions taken in relation to the identified causes?

3.1.6.3 N Are there records? 3.1.7 INF Is there the need for a cold chamber? 3.1.7.1 I Is there a cold chamber? 3.1.7.1.1 N Is the temperature controlled? 3.1.7.1.2 N Are there temperature records?

3.1.7.1.3 R

Is there an alarm system alerting about the occurrence of deviations related to the programmed temperature of the cold chamber?

3.1.7.1.4 INF Which is the temperature registered at the time of inspection? ______oC

3.2.- Specific conditions No. Qualif. Items YES NO N/A

3.2.1 N Do all the activities performed in this area meet the previously defined SOPs?

3.2.1.1 N Are there records of the critical operations defined in the respective SOPs?

3.2.2 N Do the employees wear uniforms? 3.2.2.1 N Are the uniforms clean and in good conditions?

3.2.3 N Are the scales regularly checked and periodically calibrated?

3.2.3.1 INF What is the frequency the scales are checked? _______________________

3.2.3.1.1 N Are there records?

3.2.3.1.2 N Is the verification performed with duly calibrated standard weights?

3.2.3.2 INF What is the frequency the scales are calibrated? ____________________ 3.2.3.2.1 N Are there records?

3.2.4 N Is the storage disposition correct and rational, with the purpose of preserving the integrity and identity of the materials and products?

3.2.5 Is there an area/system delimitating or restricting the use of materials/products respecting the previously defined status for:

3.2.5.1 N Quarantine? 3.2.5.2 N Approved? 3.2.5.3 N Reproved? 3.2.6 Are there areas/systems to keep materials: 3.2.6.1 N Raw materials? 3.2.6.2 N Packaging materials? 3.2.6.3 N Intermediary products? 3.2.6.4 N Bulk products? 3.2.6.5 N Finished products?

3.2.7 Is there a unique place with a device which offers safety to keep substances and products subjected to the special control regimen:

3.2.7.1 I Raw materials? 3.2.7.2 I Bulk product? 3.2.7.3 I Finished product?

3.2.8 N

Does the storage records and control system of intermediary and bulk products include the maximum storage time allowed before its packaging?

3.2.9 N Does the record and control system of expedition observe the relative sequential relation of batches and expiration dates?

3.2.10 N Are all the material and products stored within the expiration date?

3.2.11 N Is there a separated, safe and identified area to the storage of expired materials and/or products while waiting for their final destination?

3.2.11.1 N Are these materials and/or products destroyed later?

3.2.11.2 N Are there records? 3.2.12 N Is there a system to control the stock? 3.2.12.1 INF Which one? ________________________________________________

3.2.12.2 N If computerized systems are used to the management of the materials and products, does the company prove the system safety?

3.2.13 INF Are periodical inventory performed? 3.2.13.1 N Are there records?

3.2.14 R Are the materials and products stored isolated from the floor and far from the walls, to make the cleaning and conservation easier?

3.3.- Receiving and storage of raw materials No. Qualif. Items YES NO N/A

3.3.1 N Is the area occupied consistent with the volume of operations?

3.3.2 N Do all the activities performed in this area meet the previously defined SOPs?

3.3.2.1 N Are there records of the critical operations defined in the respective SOPs?

3.3.3 N Are the raw materials correctly identified by its manufacturer/supplier?

3.3.3.1 N Is the label of identification tag duly adhered to its container?

3.3.4 N When received, does each raw material batch received a registration number?

3.3.4.1 N Is the registration number used to identify the raw material until the end of its use?

3.3.5 N

Does the label or tag issued by the company allow the correct identification, visualization or control by electronic system of the raw materials status?

3.3.5.1 N Is the label or tag duly adhered to its container?

3.3.6 N

Before its release by the Quality Control, does the raw material remains in quarantine and duly identified as such?

3.3.6.1 N

In case of stocks controlled by a computerized system, is the use of raw materials in quarantine blocked until they are released by the authorized person?

3.3.7 N Is a raw material already approved and identified as such transferred to a correspondent area/system?

3.3.8 I Are the raw materials only used after release by the quality control?

3.3.9 N Is the expiration date shown in the label?

3.3.10 N

Is there a re-analysis program if raw materials, in stock, respecting the expiration date established by their manufacturer?

3.3.10.1 N When required, is the date of re-analysis indicated in the label/system?

3.3.11 N Is there a program for the Qualification of Suppliers?

3.3.11.1 N Are the active substances suppliers qualified? N

3.3.11.2 N Are there defined criteria to the program management?

3.3.12 Does the program include:

3.3.12.1 INF The evaluation of the supply background?

3.3.12.2 INF The preliminary evaluation through a questionnaire?

3.3.12.3 INF Quality audits?

3.3.13 N Are the reproved raw materials duly identified and separated?

3.4.- Receiving and Storage of packaging materials No. Qualif. Items YES NO N/A

3.4.1 N Is the area occupied consistent with the volume of operations?

3.4.2 N Do all the activities performed in this area meet the previously defined SOPs?

3.4.2.1 N Are there records of the critical operations defined in the respective SOPs?

3.4.3 N Are the packaging materials correctly identified by their manufacturer/supplier?

3.4.4 N When received, do the packaging material receive a registration number?

3.4.4.1 N Is the registration number used to identify the packaging materials until the end of their use?

3.4.5 N

Does the label or tag issued by the company allow the correct identification and visualization of the packaging materials status (reproved, quarantine and approved)?

3.4.6 N

Are all the materials batches sampled by the Quality Control, according to appropriate and trustful statistical systems?

3.4.7 N Is the amount of material sampled in accordance with the sampling procedure established?

3.4.8 N

Before its release by the Quality Control, does the packaging material remain in quarantine duly identified as such?

3.4.9 N Is a material already approved and identified as such transferred to the related area/system?

3.4.10 N Are the reproved materials identified and separated?

3.4.11 R Are the materials considered old or obsolete destroyed?

3.4.11.1 N Are there records?

3.4.12 N Is there a locked section, into the Warehouse, with restrict access to the printed material?

3.4.12.1 N Is the permission to entry this area given only to authorized persons?

3.5.- Receiving and storage of intermediary and bulk products No. Qualif. Items YES NO N/A

3.5.1 Is there an area to store: 3.5.1.1 N Intermediary products? 3.5.1.2 N Bulk products?

3.5.2 N Do all the activities performed in this area meet the previously defined SOPs?

3.5.2.1 N Are there records of the critical operations defined in the respective SOPs?

3.5.3 Are there defined procedures to receive and store intermediary and bulk products:

3.5.3.1 N Locally produced? 3.5.3.2 I Imported?

3.5.4 I

Are there locked deposits or premises, with restrict access, to intermediary and bulk products subjected to special control regimen?

3.5.5 N

Does the record and control system of the expedition of intermediary and bulk products respect the sequential batch relation and the maximum storage period established to each product?

3.5.6 N

Is the storage of intermediary and bulk products duly organized and safe, avoiding possible mixings in the control and expedition, as well as accidents with their handling?

3.5.7 N

Before their release by the Quality Control, do the intermediary and bulk products remain in quarantine and duly identified as such?

3.6.- Receiving and storage of finished products No. Qualif. Items YES NO N/A

3.6.1 N Is there an area to store the finished products?

3.6.2 N Do all the activities performed in this area meet the previously defined SOPs?

3.6.2.1 N Are there records of the critical operations defined in the related SOPs?

3.6.3 N

Does the record and control system of expeditions of the finished products respect the sequential relation of the batches and the expiration date?

3.6.4 N

Is the storage duly organized and safe, avoiding possible mixings in their control and expedition, as well as accidents when handling them?

3.6.5 N

Before their release by the Quality Control, do the finished products remain in quarantine and identified as such?

3.6.5.1 N If computerized systems are used to the management of the products, does the company prove the system safety?

3.6.6 N Are the products safely piled up?

3.6.7 I

Are there locked deposits or premises, with restrict access, to the products subjected to the special control regimen?

3.6.8 N Does the company have procedures related to the products close to the expiration date?

3.6.8.1 N Are these procedures met? 3.6.8.2 N Are there records?

3.6.9 N

Does the company have records on the distribution of products allowing the tracking of the primary distribution client(s)?

3.6.9.1 N Are all the primary distribution clients duly authorized by the competent Sanitary Authorization?

3.7.- Sampling area for raw materials No. Qualif. Items YES NO N/A

3.7.1 N Is there a specific room to the sampling of raw materials?

3.7.2 N Do all the activities performed in this area meet the previously defined SOPs?

3.7.2.1 N Are there records on the critical operations in the respective SOPs?

3.7.3 N Do the employees wear uniforms? 3.7.3.1 N Are the uniforms clean?

3.7.4 N When required, do they wear individual protection equipment?

3.7.5 N Do the premises have appropriate hygiene conditions?

3.7.6 R If required, does the area have temperature and relative humidity control?

3.7.6.1 N Are there records?

3.7.7 N

In case of deviations related to the established parameters, is an investigation done to evaluate the causes?

3.7.7.1 N Are preventive and/or corrective actions taken related to the causes identified?

3.7.7.2 N Are there records?

3.7.8 INF Is there the need of differential pressure measure equipment?

3.7.8.1 N If yes, is there one? 3.7.8.2 N Are there records? 3.7.9 INF Are sterile raw materials sampled?

3.7.9.1 N Is the sampling performed under a Laminar Flow installed in classified areas?

3.7.9.2 N Are the Laminar Flow and the area qualified?

3.7.9.3 N Are there records?

3.7.10 N Are the instruments and tools used appropriate?

3.7.10.1 N

Are the instruments and tools, with contact to the raw materials, clean and/or sterilized, before and after each use?

3.7.10.2 N Are they identified as for the cleaning status?

3.7.11 N Are the sampled containers identified?

3.7.12 Is the content identification test performed in the containers of active substances:

3.7.12.1 N In all the containers?

3.7.12.2 N In a statistical sample, in case of SPGV manufacturers, provided that the supplier is qualified?

3.7.13 N Is a content identification test performed in a statistical sample of the containers?

3.7.14 N Are the containers with samples identified, and closed after sampling?

4.- COMPLAINT No. Qualif. Items YES NO N/A

4.1 NN Is there a designee for receiving the complaints?

4.2 NN Are there SOPs to the evaluation and measures to be adopted in case of complaints?

4.3 N Is there a person responsible for the decision and measures to be adopted?

4.4 NN Is any complaint registered and fully evaluated/investigated?

4.5 N Is the person responsible for the Quality Control involved in the complaint investigation?

4.6 N

Are follow-up actions taken after the investigation and evaluation of the complaint, including the possibility of withdrawing the product?

4.7 N Is the investigation result recorded or mentioned in the batch registration of the related product?

4.8 R Are there statistical data on the complaint causes?

5.- RETURNS No. Qualif. Items YES NO N/A

5.1 N Is there a separated or restricted area to the storage of returned products?

5.2 N Is there a designee for the receiving the returns?

5.3 N Are there SOPs to the receiving, storage and investigation on the causes of the products returns?

5.4 N Are the returned products duly identified as such?

5.5 N Are the returned products inspected and/or analyzed before its final destination is defined?

5.6 N

After the inspection and/or analysis of the returned products, are the required measures taken, including the possibility of withdrawing the product?

5.7 N

Are there records of the results of the inspection and/or analysis of the returned products, including the final destinations?

6.- COLLECTION No. Qualif. Items YES NO N/A

6.1 N

Is there a separated, safe and identified area to store the products collected from market while waiting for their finzbal destination?

6.1.1 N Are the products collected from market duly identified as such?

6.2 N

Does the company have an operational system, duly structured, to collect the products with quality deviation from the market?

6.3 N Are there SOPs to the collection of products?

6.3.1 N

Does the company establish and keep the assurance of the correct application of these procedures systematic?

6.4 I

Do the records related to the distributors allow the tracking of their products viewing their effective collection?

6.5 I In case of withdrawal, for quality deviation, are the sanitary authorities in charge immediately informed?

6.6 N Is there a responsible person for the coordination, performance of these procedures?

6.7 N

If the designee does not belong to the Quality Control and is not the Responsible Technician, are these ones informed about the operations performed?

6.8 N Are immediate actions taken to the withdrawal of the product all over the area it was distributed?

6.9 N Are records of the products collection from the market kept, including the investigation of the causes?

6.10 N Does the information available allow to determine the percentage of the expedited product collection?

6.11 N Are there records on the products collected from the market destination?

7.- WATER SYSTEMS AND INSTALLATIONS 7.1.- Drinkable water

No. Qualif. Items YES NO N/A 7.1.1 Which is the origin of the water used in the company: 7.1.1.1 INF Public System? 7.1.1.2 INF Artesian Well?

7.1.2 INF Does the company have a water reservoir?

7.1.3 INF Before the water is stored is there any treatment?

7.1.3.1 INF Which one? __________________________________________

7.1.4 N Is a cleaning performed in the water reservoirs?

7.1.4.1 INF What is the frequency? _________________________________ 7.1.4.2 N Are there records?

7.1.4.3 R Are there SOPs for the cleaning of the water reservoirs?

7.1.5 INF Are the drinkable water control parameters in accordance with the limits established by the current legislation?

7.1.6 N Are physical-chemical tests of the drinkable water performed?

7.1.6.1 INF Which ones? ___________________________________________________

7.1.6.2 INF What is the frequency? ___________________________________________

7.1.6.3 N Are there records?

7.1.7 N Are microbiological tests of the drinkable water performed?

7.1.7.1 INF What is the frequency? ___________________________________________

7.1.7.2 N Are there records?

7.1.8 N

Are water samples collected periodically in different points of the manufacturing site, including in the water fountain, to perform the microbial counting?

7.1.8.1 N Are there records?

7.1.8.2 N In case of results above the established limits is an investigation performed to evaluate the causes?

7.1.8.2.1 N Are preventive and/or corrective actions taken in relation to the causes identified?

7.1.8.2.2 N Are there records? 7.2- Purified water

No. Qualif. Items YES NO N/A

7.2.1 N

Does the company have a production system to Purified Water, meeting the defined specifications in the Pharmacopoeia adopted by the Ministry of Health?

7.2.1.1 INF Method to obtain purified water:___________________________________ 7.2.1.2 INF Type of equipment: ____________________________________________ 7.2.1.2.1 INF What is the capacity in liters/hour? _________m3 : _____________Liters

7.2.1.3 N Is there qualified personnel to operate the system?

7.2.2 R

Is there an updated diagram on the system of production and distribution of purified water, including the system components, sampling points and using points?

7.2.3 INF Is the water supplying the purified water system treated?

7.2.3.1 INF How? ______________________________________________________

7.2.4 N Do all the activities performed in this are meet the previously defined SOPs?

7.2.5 INF Is there a deposit for the purified water? 7.2.5.1 INF What is its capacity? _________ m3 : _____________ Liters 7.2.5.2 INF For how long it is stored? _____________/ hours

7.2.5.3 INF Is there a purified water recirculation system?

7.2.6 N Is there any treatment to avoid the microbiological contamination?

7.2.6.1 INF Which one? _________________________________________________

7.2.7 N Are there in line instruments to manage the quality parameters of the water?

7.2.7.1 INF Which ones? _______________________________________________ 7.2.8 N Are physical-chemical tests performed? 7.2.8.1 INF Which ones? _____________________________________________ 7.2.8.2 INF What is the frequency?________________________________________ 7.2.8.3 N Are there records? 7.2.9 N Are microbiological tests performed? 7.2.9.1 INF What is the frequency? _______________________________________ 7.2.9.2 N Are there records?

7.2.10 N In case of results above the established limits is an investigation performed to evaluate the causes?

7.2.10.1 N Are preventive and/or corrective actions taken in relation to the identified causes?

7.2.10.2 N Are there records?

7.2.11 INF What is the material used to build the distribution lines of purified water?

7.2.12 INF Is the water produced used as raw material for non-sterile products?

7.2.13 N Is there a procedure to release the water used in the production?

7.2.13.1 N Are there records?

7.2.14 INF Is the water produced used as feeding source to the production system for water for injection?

7.2.15 N Is a sanitization of the system performed? 7.2.15.1 INF What is the frequency? ________________________________________ 7.2.15.2 N Are there records?

7.2.16 N Is a preventive maintenance performed in the system equipment?

7.2.16.1 INF What is the frequency? _________________________________________ 7.2.16.2 N Are there records? 7.2.17 R Are there filtrating means in the system? 7.2.17.1 INF Which ones? _________________________________________________

7.2.18 N Are there records on the changing of the filtrating means?

7.2.19 N Is a sanitization of the filtrating means performed?

7.2.19.1 INF What is the frequency? _________________________________________ 7.2.19.2 N Are there records?

7.2.20 N Are the measuring and/or control instruments installed in line calibrated?

7.2.21 INF Is there an UV unit installed in the system?

7.2.21.1 N Are there records on the changing of the UV unit lamps?

7.2.22 N Are there records on the regeneration of ionic exchange resins?

7.2.23 N Is the production system of Purified Water validated?

7.2.24 INF What is the period of evaluation tests established in the approved protocol? ___

7.2.25 N Did the results of the tests conducted during the validation meet the acceptance criteria established in the approved protocol?

7.2.26 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

7.2.27 N Is there a pre-established frequency to the periodical revalidation?

7.2.27.1 INF Which one? __________________________________________________

7.2.27.2 N Are the results obtained in the revalidation in accordance with the approved protocol?

7.3.- Water for injections No. Qualif. Items YES NO N/A

7.3.1 I

Does the company have a system to the production of Water for Injection according to the processes established by the current issues of the European Pharmacopoeia or the U.S. Pharmacopoeia?

7.3.1.1 INF Method to obtain water for injection: ______________________________

7.3.1.2 INF Type of equipment: ___________________________________________

7.3.1.2.1 INF What is the capacity in liters/hour? ______ m3; _____________ Liters

7.3.2 I Is the water produced used as raw material for sterile products?

7.3.3 N Is there qualified personnel to operate the system?

7.3.4 N Do all the activities performed in this area meet the previously defined SOPs?

7.3.5 INF Is there a deposit for water for injection? 7.3.5.1 INF What is the deposit capacity? ________ m3; _________ Liters

7.3.5.2 INF What is the material used in the building of the deposit?

7.3.5.3 INF For how long is the water stored? ______________ hours 7.3.5.4 INF Storage temperature: _________________ oC

7.3.6 INF Is there a closed circulation system (looping)?

7.3.6.1 N

Does the material used in the piping in the distribution lines assure the water purity and the specified level of microbial contamination?

7.3.6.1.1 INF Which is the material? 7.3.6.2 N Are the circulation pumps sanitary?

7.3.6.3 N Are the valves existing in the circuit sanitary?

7.3.7 INF If there is no closed circulation system, how is the water for injection transported? ______________________________________________

7.3.8 Are there apparatus in the system to measure: 7.3.8.1 INF Temperature? 7.3.8.2 INF pH? 7.3.8.3 INF Conductivity? 7.3.8.4 INF Total organic carbon (TCO)? 7.3.9 Are there records on: 7.3.9.1 N pH? 7.3.9.2 N Conductivity? 7.3.9.3 N Total organic carbon? 7.3.10 INF Is there any kind of filter in the system?

7.3.10.1 INF Which one? _________________________________________________

7.3.10.2 N Are there records on the exchange of filtrating means?

7.3.10.3 N Is the sanitization of the filtrating means performed?

7.3.10.3.1 INF What is the frequency? ________________________________________

7.3.10.3.2 N Are there records? 7.3.11 N Are physical-chemical tests performed?

7.3.11.1 INF Which ones? ________________________________________________

7.3.11.2 INF What is the frequency? ________________________________________

7.3.11.3 N Are there records? 7.3.12 N Are microbiological tests performed?

7.3.12.1 INF What is the frequency? ________________________________________

7.3.12.2 N Are there records? 7.3.13 N Are endotoxin tests performed?

7.3.13.1 INF What is the frequency? ________________________________________

7.3.13.2 N Are there records?

7.3.14 N In case of results above the established limits, is an investigation to evaluate the causes performed?

7.3.14.1 N Are preventive and/or corrective actions taken in relation to the identified causes?

7.3.14.2 N Are there records?

7.3.15 N Is there a procedure to the release of the water used in the production?

7.3.15.1 N Are there records?

7.3.16 N Is the production system of water for injection sanitized?

7.3.16.1 INF What is the frequency?________________________________________

7.3.16.2 N Are there records?

7.3.17 N Is a preventive maintenance performed in the system equipment?

7.3.17.1 INF What is the frequency? _______________________________________

7.3.17.2 N Are there records?

7.3.18 N Is the production system of Water for Injection validated?

7.2.19 INF What is the period of evaluation tests established in the approved protocol? _____________________________________________________

7.2.20 N

Do the results of the tests conducted during the validation meet the acceptance criteria established in the approved protocol?

7.3.21 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

7.3.22 N Is there a pre-established frequency to the periodical revalidation?

7.3.22.1 INF Which one? _________________________________________________

7.3.22.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.- PRODUCTION 8.1. General considerations

No. Qualif. Items YES NO N/A 8.1.1 N Is there a production planning?

8.1.2 I Are there authorized Standard/Master Formula for each product and batch size to be manufactured?

8.1.3 I

Is the Production Order for each batch of product faithfully based on the established instructions by the Master/Standard Formula?

8.1.4 I Are records on all the produced batches kept?

8.1.5 N Are the production areas consistent with the operations volume?

8.1.6 N

Does the production areas design allow the effective cleaning and maintenance, in order to avoid cross-contamination or any adverse effect on the products quality?

8.1.7 N

Are the maintenance and repair operations of equipment in the production areas performed in a way to avoid any risk to the products?

8.1.8 N Are the premises built in a way that allows the protection against the entrance of insects and other animals?

8.1.9 N

When required, are there instruments to control the temperature, humidity and differential pressure between the areas?

8.1.9.1 N Are there records?

8.1.9.2 N In case of deviations, in relation to the established limits, is an investigation performed to evaluate the causes?

8.1.9.3 N Are preventive and/or corrective actions taken in relation to the investigated causes?

8.1.9.4 N Are there records?

8.1.10 N Is the illumination in the production areas appropriate to the activities developed?

8.1.11 N Is the ventilation in the production areas appropriate to the activities developed?

8.1.12 N

Are the walls, ceiling and floor covered with a easily washable material and free from cracks or desquamating painting?

8.1.13 N Is the floor plain, impermeable and easy to clean?

8.1.14 N Are the areas clean?

8.1.18 N Does the company have SOPs to all the activities developed in the production areas?

8.1.19 N Are the SOPs related to the activities of each area available in the respective working place?

8.1.20 N Is there a procedure regulating the entrance of non-authorized persons in the production areas?

8.1.21 N Do the personnel wear uniform?

8.1.21.1 N Are the uniforms clean and in good conservation status?

8.1.22 N Do the employees wear the appropriate garments to the production activities, only in these areas?

8.1.23 N Is the company responsible for the washing of the employees uniforms?

8.1.24 N When required, is the individual protection equipment (IPE) worn?

8.1.25 INF Are there drains in the production areas?

8.1.25.1 N If yes, are they siphoned?

8.1.25.2 N Are there drain cleaning and disinfection records?

8.1.26 R Are the garbage containers identified and covered?

8.1.27 N Is the equipment distribution ordered and rational?

8.1.28 N Are the equipment placed in order to avoid cross-contamination?

8.1.29 N Are the circulation areas free?

8.1.30 N

Are all the equipment in use in the production identified with the product name, batch number and production step?

8.1.31 N Are the measuring and/or control instruments calibrated?

8.1.31.1 N Are there records?

8.1.32 N

Are the in-process control tests performed in the frequencies established in the related operation procedures?

8.2.- Weighing and measuring area No. Qualif. Items YES NO N/A

8.2.1 N Is there an area for the weighing and measuring activities?

8.2.2 N Does the weighing and measuring area have an independent exhaustion system?

8.2.3 N Is there a cross-contamination prevention system during the weighing and/or measuring operation?

8.2.4 N Is the contamination risk with the environment avoided?

8.2.5 I Is there an specific area to weigh highly sensitizing substances?

8.2.5.1 N Does the area have negative pressure?

8.2.6 N

Are the materials used for weighing and/or measuring (containers, spatulas, pipettes, etc.) clean, identified as such, protected and stored in a defined place?

8.2.7 N Are the scales regularly verified and periodically calibrated?

8.2.7.1 INF Which is the frequency they are verified? __________________________

8.2.7.1.1 N Are there records?

8.2.7.1.2 N Are the verifications performed with duly calibrated standard weights?

8.2.7.2 INF Which is the frequency of calibration? ________________________________

8.2.7.2.1 N Are there records?

8.2.8 N Are the measuring materials calibrated?

8.2.8.1 N Are there records?

8.2.9 N

During the weighing and/or measuring operations, do the employees wear protection (goggles, caps, masks, etc.)?

8.2.10 I Is the weighing and/or measuring operation performed in accordance with a Production Order?

8.2.11 N

Are the outer package of raw materials to be weighed and/or measured cleaned before entering the weighing areas?

8.2.12 N

Are the packages with the product of the raw materials used in the weighing and/or measuring operation well closed to protect their contents and to avoid their contamination?

8.2.13 N Is the weighing or measuring operation of raw materials checked?

8.2.13.1 N Are there records?

8.2.14 N Are the weighed and/or measured materials identified?

8.2.14.1 INF Which is the system used? ______________________________________

8.2.15 N Is there physical separation of the weighed and/or measured materials for each production batch?

8.3.- Solid Products 8.3.1.- General information

No. Qualif. Items YES NO N/A

8.3.1.1 INF To specify the pharmaceutical presentations produced: ________________________________________________ __________________________

8.3.1.2 N Is there an specific area to the manufacturing of solid products?

8.3.2. Production No. Qualif. Items YES NO N/A

8.3.2.1 I Are the instructions of the Production Order accurately followed?

8.3.2.1.1 N Are all the production steps registered and signed by their performer?

8.3.2.1.2 N Are all the production critical steps signed by the indicated supervisor?

8.3.2.2 INF Are there measuring scales and containers in the production area?

8.3.2.2.1 N Are they periodically calibrated?

8.2.7.2.1.1 INF What is the frequency of calibrations? ______________________________

8.3.2.2.1.2 N Are there records? 8.3.2.2.2 N Are the scales periodically checked? 8.3.2.2.2.1 N Are there records?

8.3.2.2.2.2 N Are the verifications performed with duly calibrated standard weights?

8.3.2.3 N When required, do the equipment used in the production processes have a dust aspiration system?

8.3.2.3.1 INF What is the destinations of these wastes? ___________________________________

8.3.2.4 N

Are all the containers used in the production of a product batch duly identified in accordance with their contents?

8.3.2.5 N After their use, are all the tools, containers and equipment hygienically cleaned and identified as such?

8.3.2.6 Mixing/homogenization step

8.3.2.6.1 INF Type(s) of equipment: ______________________________________

8.3.2.6.2 N Are in-process control tests performed?

8.3.2.6.2.1 INF Which ones? _______________________________________ 8.3.2.6.2.2 N Are there records? 8.3.2.7 Agglutination step

8.3.2.7.1 INF Type(s) of equipment: ______________________________________

8.3.2.8 Compactation step

8.3.2.8.1 INF Type(s) of equipment: ______________________________________

8.3.2.9 Granulation step 8.3.2.9.1 INF Type(s) of equipment: ________________________________

8.3.2.9.2 N Are in-process control tests performed?

8.3.2.9.2.1 INF Which ones? _______________________________________ 8.3.2.9.2.2 N Are there records?

8.3.2.10 Drying step

8.3.2.10.1 INF Is the equipment used in the granulated drying the Drying Chamber?

8.3.2.10.1.1 I Does the granulated drying chamber receive only product of a same batch?

8.3.2.10.2 INF Is the equipment used in the granulated drying the fluid bed?

8.3.2.10.2.1 N Are the filters designated to each product category?

8.3.2.10.3 INF Are other drying equipment used?

8.3.2.10.3.1 INF Which ones? ______________________________________________

8.3.2.10.4 N Do the granulated drying equipment have instruments to record the temperature and time for drying?

8.3.2.10.4.1 N Are there records? 8.3.2.10.4.2 N Are the record instruments calibrated?

8.3.2.10.5 N Are in-process control tests performed?

8.3.2.10.5.1 INF Which ones? _____________________________________________

8.3.2.10.5.2 N Are there records? 8.3.2.11 Encapsulating step

8.3.2.11.1 INF Type(s) of equipment: ______________________________________

8.3.2.11.2 N Are in-process control tests performed?

8.3.2.11.2.1 INF Which ones? _____________________________________________

8.3.2.11.2.2 N Are there records? 8.3.2.12 Compression step

8.3.2.12.1 INF Type(s) of equipment: ______________________________________

8.3.2.12.2 N Are in-process control tests performed?

8.3.2.12.2.1 INF Which ones? ______________________________________________

8.3.2.12.2.2 N Are there records? 8.3.2.13 Coating steps

8.3.2.13.1 INF Type(s) of equipment: ______________________________________

8.3.2.13.2 N Are tests performed after the coating?

8.3.2.13.2.1 INF Which ones? ______________________________________________

8.3.2.13.2.1.1 N Are there records?

8.3.2.13.3 N If required, are tests performed through the process?

8.3.2.13.3.1 INF Which ones? ______________________________________________

8.3.2.13.3.2 N Are there records?

8.3.2.14 INF Is there a storage place of intermediary products in the production area?

8.3.2.15 N Is there a place/system for quarantine of intermediary products which delimitates or restricts their use?

8.3.2.16 INF Is there a storage place for bulk products in the production area?

8.3.2.17 N Is there a place/system of quarantine to the bulk products which delimitates or restricts their use?

8.3.2.18 N Are the recipients containing these products well closed and identified?

8.3.2.18.1 INF Which is the identification system used? _________________________

8.3.2.19 N Does the Validation Master Plan include all the steps of the process of solids production?

8.3.2.19.1 N Are there approved protocol to the ongoing validations?

8.3.2.20 What kind of validation is expected: 8.3.2.20.1 INF Prospective?

8.3.2.20.1.1 INF How many batches will be evaluated? __________________________

8.3.2.20.2 INF Retrospective?

8.3.2.20.2.1 INF What is the number of batches considered? ______________________

8.3.2.20.2.2 N Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.3.2.20.3 INF Concurrent?

8.3.2.20.3.1 INF How many batches will be considered? ________________________

8.3.2.21 N Do the results of the tests meet the acceptance criteria established in the approved protocol?

8.3.2.22 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.3.2.23 N Is there a pre-established frequency to the periodical revalidation?

8.3.2.23.1 INF Which one? ___________________________________________

8.3.2.23.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.3.2.24 N Are the companies which hold the generic products registration with all the steps of the process of solids production of this category validated?

8.3.3. Packaging 8.3.3.1 Packaging area

No. Qualif. Items YES NO N/A

8.3.3.1.1 N Is there an exclusive area to the primary packaging of drugs under the solid pharmaceutical presentation?

8.3.3.1.2 INF Are there places requiring controlled environmental conditions?

8.3.3.1.2.1 If required, are there instruments to control: 8.3.3.1.2.1.1 N Temperature?

8.3.3.1.2.1.2 N Air relative humidity?

8.3.3.1.2.1.3 N Differential pressure of the areas?

8.3.3.1.2.1.4 N Are there records?

8.3.3.1.3 N Are the packaging lines identified in accordance with the product that is being packaged?

8.3.3.1.4 I Are the instructions of Production Order/Packaging Order accurately followed?

8.3.3.1.5 N Are the packaging lines released before their use?

8.3.3.1.5.1 N Are there records?

8.3.3.1.6 N When required, are there extraction system of dusts from the area, arising from the packaging operations?

8.3.3.1.7 N When required, do the equipment used in the dusts filling process have a dust aspiration system?

8.3.3.1.7.1 INF What is the destination of these wastes?

8.3.3.1.8 N Are controls performed during the packaging process?

8.3.3.1.8.1 INF Which ones? ______________________________________________ 8.3.3.1.8.2 N Are there records?

8.3.3.1.9 N Is an in line inspection performed during the packaging process?

8.3.3.1.9.1 N Are there records?

8.3.3.1.10 N Is the reconciliation among the theoretical amount of printed, filling materials and bulk products and the actual amount used?

8.3.3.1.10.1 N Are there records? 8.3.3.2. Labeling

No. Qualif. Items YES NO N/A

8.3.3.2.1 I Is the access to the labels, in the packaging area, allowed only to duly authorized persons?

8.3.3.2.2 N

Are the labels inspected to check if they correspond to the product to be labeled and the conformity with the Production Order/Packaging Order, before delivered to the packaging line?

8.3.3.2.3 N Are the labeling machines inspected and released before their use?

8.3.3.2.3.1 N Are there records?

8.3.3.2.4 I Are the labels printed with unused batch number and expiration dates destroyed?

8.3.3.2.4.1 N Are there records?

8.3.3.2.5 N

Are the quantities of labels received, used, including the damaged ones and the destroyed ones registered?

8.3.3.2.6 I

Are all the differences among the number of labels received, number of labels used, including the damaged ones and the destroyed ones investigated?

8.3.3.2.6.1 N Are there records?

8.3.3.2.7 N Are the non-printed labels with the batch number and expiration date returned to the warehouse?

8.3.3.2.7.1 N Is there a person responsible for this return?

8.3.3.2.7.2 N Are there records? 8.4.- SEMI-SOLID PRODUCTS 8.4.1. General information

No. Qualif. Items YES NO N/A 8.4.1.1 INF Specify the pharmaceutical presentations produced:

_______________________________________________ ________________________

8.4.1.2 N Is there an area for the manufacturing of semi-solid products? 8.4.2. Production

No. Qualif. Items YES NO N/A

8.4.2.1 INF Are there measuring scales and containers in the production area?

8.4.2.1.1 N Are they regularly calibrated? 8.4.2.1.1.1 N Are there records? 8.4.2.1.2 N Are they regularly verified? 8.4.2.1.2.1 N Are there records?

8.4.2.1.2.2 N Are the verifications performed with duly calibrated standard weights?

8.4.2.2 I Is the Production Order accurately followed?

8.4.2.2.1 N Are all the production steps registered and signed by their performer?

8.4.2.2.2 N Are all the production critical steps signed by the indicated supervisor?

8.4.2.3 N

Are all the containers used in the production of a product batch duly identified in accordance to their content?

8.4.2.4 N Are all the equipment used in the production of a batch identified in accordance with the product?

8.4.2.5 N After their use, are all the tools, containers, and equipment hygienically cleaned and identified as such?

8.4.2.6 N

Are the equipments properly placed in order to avoid mixings/cross-contamination when simultaneous batches of different products are manufactured?

8.4.2.7 N Are in-process control tests performed?

8.4.2.7.1 INF Which ones? ______________________________________ 8.4.2.7.2 N Are there records?

8.4.2.8 INF Is there a place to store the bulk products in the production area?

8.4.2.9 N Is there a place/system to quarantine the bulk products which delimitates or restricts their use?

8.4.2.10 N Are the recipients containing these products well closed and identified?

8.4.2.10.1 INF What is the identification system used?________________________

8.4.2.11 N Does the Validation Master Plan include all the steps of the process of semi-solids production?

8.4.2.11.1 N Are there approved protocol to the ongoing validations?

8.4.2.12 What kind of validation is expected: 8.4.2.12.1 INF Prospective?

8.4.2.12.1.1 INF How many batches will be evaluated? __________________________

8.4.2.12.2 INF Retrospective?

8.4.2.12.2.1 INF What is the number of batches considered? ______________________

8.4.2.12.2.2 N

Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.4.2.12.3 INF Concurrent?

8.4.2.12.3.1 INF How many batches will be considered? _________________________

8.4.2.13 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.4.2.14 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.4.2.15 N Is there a pre-established frequency to the periodical revalidation?

8.4.2.15.1 INF Which one? _____________________________________

8.4.2.15.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.4.2.16 Sterile semi-solid products:

8.4.2.16.1 INF Is the preparation of sterile semi-solid products performed in an open system?

8.4.2.16.1.1 N Are they prepared in a clean area grade C (class 10,000)?

8.4.2.16.2 INF Is the preparation of sterile semi-solid products performed in a closed system?

8.4.2.16.2.1 N Are they prepared in a clean area, grade D (class 100,000)?

8.4.2.16.3 N Are they filled in a clean area, grade D (class 10,000)?

8.4.2.16.4 INF What is the process used to assure the sterility of the products? __________

8.4.2.17 N Does the Validation Master Plan include the steps of the process of sterile semi-solids production?

8.4.2.18 N Are there approved protocols to the ongoing validations?

8.4.2.19 What type of validation is expected: 8.4.2.19.1 INF Prospective? 8.4.2.19.1.1 INF How many batches will be evaluated? ____________________ 8.4.2.19.2 INF Retrospective?

8.4.2.19.2.1 INF How many batches will be considered? __________________________

8.4.2.19.2.2 N

Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.4.2.19.3 INF Concurrent? 8.4.2.19.3.1 INF How many batches will be evaluated?

8.4.2.20 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.4.2.21 N Were the deviations found in relation to the statements established in the approved protocol duly investigated?

8.4.2.22 N Is there a pre-established frequency to the periodical revalidation?

8.4.2.22.1 INF Which one? _______________________________________

8.4.2.22.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.4.3. Filling 8.4.3.1. Filling area

No. Qualif. Items YES NO N/A

8.4.3.1.1 N Is there an specific area to the filling of drugs in the sterile semi-solid pharmaceutical presentation?

8.4.3.1.2 N Are the filling lines identified according to the product that is being packaged?

8.4.3.1.3 I Are the Production Order instructions accurately followed?

8.4.3.1.4 N Are the filling lines inspected and released before their use?

8.4.3.1.4.1 N Are there records?

8.4.3.1.5 N Are in-process controls performed during the filling operations?

8.4.3.1.5.1 INF Which ones? ___________________________________________

8.4.3.1.5.2 N Are there records?

8.4.3.1.6 N

Is the reconciliation among the theoretical quantity of filling materials (printed or not) and bulk products and the actual quantity used?

8.4.3.1.6.1 N Are there records? 8.4.4 Packaging 8.4.4.1 Packaging area

No. Qualif. Items YES NO N/A

8.4.4.1.1 N

Is there an exclusive area to the secondary packaging of drugs in the semi-solid pharmaceutical presentation?

8.4.4.1.2 N Are the packaging lines identified according to the products that is being packaged?

8.4.4.1.3 I Are the Production Order/Packaging Order instructions accurately followed?

8.4.4.1.4 N Are the packaging lines released before use?

8.4.4.1.4.1 N Are there records?

8.4.4.1.5 N Is a line inspection performed during the packaging process?

8.4.4.1.5.1 N Are there records?

8.4.4.1.6 N

Is the reconciliation among the theoretical quantity of printed, filling materials and bulk product and the actual quantity used?

8.4.4.1.6.1 N Are there records? 8.5.- LIQUID PRODUCTS 8.5.1. General information

No. Qualif. Items YES NO N/A 8.5.1.1 INF Specify the pharmaceutical presentations produced:

_________________________________________________ _______________________

8.5.1.2 N Is there an area to the manufacturing of liquid products? 8.5.2. Production

No. Qualif. Items YES NO N/A

8.5.2.1 INF Are there measuring scales and containers in the production area?

8.5.2.1.1 N Are they regularly calibrated? 8.5.2.1.1.1 N Are there records? 8.5.2.1.2 N Are the scales regularly checked? 8.5.2.1.2.1 N Are there records?

8.5.2.1.2.2 N Are the verifications performed with duly calibrated standard weights?

8.5.2.2 I Are the Production Order instructions accurately followed?

8.5.2.2.1 N Are all the production steps registered and signed by their performer?

8.5.2.2.2 N Are all the production critical steps signed by the indicated supervisor?

8.5.2.3 N

Are all the containers used in the production of a product batch duly identified in accordance with their contents?

8.5.2.4 N After use, are all the tools, containers, and equipment hygienically cleaned and identified as such?

8.5.2.5 N

Are all the equipment placed correctly in order to avoid mixings/cross-contamination when simultaneous batches of different products are manufactured?

8.5.2.6 N Is the water used in the production at least purified?

8.5.2.7 R Are the solutions filtered? 8.5.2.7.1 INF Type of filter: ________________________________________

8.5.2.7.2 N Are there records on the filters sanitization?

8.5.2.8 N Are in-process control tests performed?

8.5.2.8.1 INF Which ones? ________________________________________ 8.5.2.8.2 N Are there records?

8.5.2.9 INF Is there a place to store the bulk products in the production area?

8.5.2.10 N Is there a place/system to quarantine the bulk products which delimitates or restricts their use?

8.5.2.11 N Are the recipients containing these products well closed and identified?

8.5.2.12 N Does the Validation Master Plan include all the steps of the process of liquids production?

8.5.2.13 N Are there approved protocols to the ongoing validations?

8.5.2.14 What kind of validation is expected: 8.5.2.14.1 INF Prospective?

8.5.2.14.1.1 INF How many batches will be evaluated? __________________________

8.5.2.14.2 INF Retrospective?

8.5.2.14.2.1 INF How many batches will be considered? _________________________

8.5.2.14.2.2 N

Were all the batches considered in the Retrospective Validation produced according to the operational parameters and specifications?

8.5.2.14.3 INF Concurrent? 8.5.2.14.3.1 INF How many batches will be evaluated?

8.5.2.15 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.5.2.16 N Were the deviations found in relation to the parameters established in the approved protocol were duly investigated?

8.5.2.17 N Is there a pre-established frequency to the periodical revalidation?

8.5.2.17.1 INF Which one? _____________________________________________

8.5.2.17.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.5.2.18 N

Are the companies which hold the generic products registration with all of their steps of the liquids production process of this category?

8.5.3-Packaging 8.5.3.1 Filling area

No. Qualif. Items YES NO N/A

8.5.3.1.1 N Is there an specific area to the filling of drugs in the liquid pharmaceutical presentation?

8.5.3.1.2 I Are the instructions of the Production Order accurately followed?

8.5.3.1.3 N Are the filling lines inspected and released before their use?

8.5.3.1.3.1 N Are there records?

8.5.3.1.4 R Are in-process controls performed during the filling operations?

8.5.3.1.4.1 INF Which ones? _____________________________________________ 8.5.3.1.4.2 N Are there records?

8.5.3.1.5 N Is the reconciliation among the theoretical quantity of the printed, filling materials and bulk product and the actual quantity used?

8.5.3.1.5.1 N Are there records? 8.5.3.2. Labeling

No. Qualif. Items YES NO N/A

8.5.3.2.1 I Is the access to the labels, in the packaging area, allowed only to duly authorized persons?

8.5.3.2.2 N

Are the batches inspected to check if they correspond to the product to be labeled and the accordance with the Production Order/Packaging Order, before being delivered to the packaging line?

8.5.3.2.3 N Are the labeling machines inspected and released before use?

8.5.3.2.3.1 N Are there records?

8.5.3.2.4 N Are the printed batches with unused batch number and expiration date destroyed?

8.5.3.2.4.1 N Are there records?

8.5.3.2.5 N Are the quantities of labels received, used, including the damaged and destroyed ones?

8.5.3.2.6 I

Are all the differences among the number of labels received, labels used, including the damaged ones and the destroyed ones investigated?

8.5.3.2.6.1 N Are there records?

8.5.3.2.7 N Are the labels non-printed with batch number and expiration date returned to the warehouse?

8.5.3.2.7.1 N Is there a person responsible for this return?

8.5.3.2.7.2 N Are there records? 8.5.3.3 - Secondary Package

No. Qualif. Items YES NO N/A

8.5.3.3.1 N

Is there an exclusive area to the secondary packaging of drugs in the non-sterile liquid pharmaceutical presentation?

8.5.3.3.2 N Are the packaging lines identified in accordance with the product that is being packaged?

8.5.3.3.3 I Are the Production Order/Packaging Order instructions accurately followed?

8.5.3.3.4 N Are the packaging lines released before use?

8.5.3.3.4.1 N Are there records?

8.5.3.3.5 N Is an in line inspection performed during the packaging process?

8.5.3.3.5.1 N Are there records?

8.5.3.3.6 N

Is the reconciliation among the theoretical quantity of printed, filling materials and bulk product and the actual quantity used?

8.5.3.3.6.1 N Are there records? 8.6. Products of therapeutic classes requiring special production conditions in addition to the requirements already established by the production line 8.6.1.- Hormone products

No. Qualif. Items YES NO N/A

8.6.1.1 INF

Specify the pharmaceutical presentations produced (solid, semi-solid, liquid, injection): ________________________________________________ ______________________________ _____________________________________

8.6.1.2 N Is there an exclusive and separated area to the production of hormone products?

8.6.1.3 I Is the production of these products done avoiding cross-contamination?

8.6.1.4 I Is the air insufflating and exhausting system independent from the ones present at the other areas or premises?

8.6.1.5 N Does the air exhaustion system have devices to avoid the environment contamination?

8.6.1.6 N Does the production area have a negative air pressure in comparison to the other appended areas?

8.6.1.6.1 N Are there records of the differential pressure?

8.6.1.7 N Do the employees wear individual protection equipment during all the production process?

8.6.1.8 N Are specific and periodical medical exams performed in people manipulating hormones?

8.6.1.8.1 N Are there records?

8.6.1.9 N Are periodical shifts performed among the employees in the production area?

8.6.1.9.1 INF What is the periodicity? ____________________________

8.6.1.10 N Does the Validation Master Plan include all the steps of the process of hormone products production?

8.6.1.10.1 N Are there approved protocols to the ongoing validations? 8.6.1.11 What kind of validation is expected: 8.6.1.11.1 INF Prospective? 8.6.1.11.1.1 INF How many batches will be evaluated?__________________________ 8.6.1.11.2 INF Retrospective? 8.6.1.11.2.1 INF How many batches will be considered? _________________________

8.6.1.11.2.2 N Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.6.1.11.3 INF Concurrent? 8.6.1.11.3.1 INF How many batches will be evaluated? ________________________

8.6.1.12 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.6.1.13 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.6.1.14 N Is there a pre-established frequency to the periodical revalidation?

8.6.1.14.1 INF Which one? __________________________________________

8.6.1.14.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.6.2.- Products containing highly active substances (e.g., prostaglandins, thalidomide, immunosuppressants, some psychoactive substances and others)

No. Qualif. Items YES NO N/A

8.6.2.1 INF Specify the pharmaceutical presentations produced: ______________________________________________ _______________________

8.6.2.2 INF Is there an exclusive area to the production of products containing highly active substances?

8.6.2.3 I Is the production of these products performed avoiding cross-contamination?

8.6.2.4 I If there is an exclusive room, is the air insufflating and exhausting system independent from the ones present in the other areas or premises?

8.6.2.5 N Does the air exhaustion system have devices to avoid the environment contamination?

8.6.2.6 N Do the employees wear individual protection equipment during all the production process?

8.6.2.7 N Are periodical specific medical exams performed in the people handling products subjected to the special control regimen?

8.6.2.7.1 N Are there records?

8.6.2.8 N Are the cleaning procedures of the equipment used in the production of products subjected to special control regimen validated?

8.6.2.9 N If there is an exclusive room, does the Validation Master Plan includes all the steps of the production of products containing highly active substances?

8.6.2.9.1 N Are there approved protocols to the ongoing validations? 8.6.2.10 What kind of validation is expected: 8.6.2.10.1 INF Prospective? 8.6.2.10.1.1 INF How many batches will be evaluated?__________________________ 8.6.2.10.2 INF Retrospective? 8.6.2.10.2.1 INF How many batches will be considered? __________

8.6.2.10.2.2 N Were all the batches considered in the Retrospective validation produced according to the same operational parameters and specifications?

8.6.2.10.3 INF Concurrent? 8.6.2.10.3.1 INF How many batches will be evaluated?

8.6.2.11 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.6.2.12 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.6.2.13 N Is there a pre-established frequency to the periodical revalidation?

8.6.2.13.1 INF Which one? ___________________________________

8.6.2.13.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.6.3.- Antibiotic products non-betalactamic

No. Qualif. Items YES NO N/A

8.6.3.1 INF Specify the pharmaceutical presentations produced: ______ ________________________________________________

8.6.3.2 INF Is there an exclusive area to the production of non-betalactamic antibiotics?

8.6.3.5 I Is their production performed avoiding the cross-contamination?

8.6.3.3 I If there is an exclusive area, is the air insufflating and exhausting system independent from the other ones present in the other areas or premises?

8.6.3.4 N Does the air exhausting system have devices to avoid the environment contamination?

8.6.3.6 N Do the employees wear individual protection equipment during all the production process?

8.6.3.7 N Are periodical specific medical exams performed in the people handling antibiotics?

8.6.3.7.1 N Are there records?

8.6.3.8 N Are the cleaning procedures of the equipment used in the production of non-betalactamic antibiotics validated?

8.6.3.9 N Does the Validation Master Plan include the production of non-lactamic antibiotic products?

8.6.3.9.1 N Are there approved protocols to the ongoing validations? 8.6.3.10 What kind of validation is expected: 8.6.3.10.1 INF Prospective? 8.6.3.10.1.1 INF How many batches will be evaluated? 8.6.3.10.2 INF Retrospective? 8.6.3.10.2.1 INF How many batches will be considered?

8.6.3.10.2.2 N Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.6.3.10.3 INF Concurrent? 8.6.3.10.3.1 INF How many batches will be evaluated?

8.6.3.11 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.6.3.12 N Were the deviations found in relation to the parameters established in the approved protocol duly identified?

8.6.3.13 N Is there a pre-established frequency to the periodical revalidation?

8.6.3.13.1 INF Which one? ________________________________

8.6.3.13.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.6.4.- Penicillin products

No. Qualif. Items YES NO N/A 8.6.4.1 INF Specify the pharmaceutical presentations produced: ________________ 8.6.4.2 The production of penicillin products is performed: 8.6.4.2.1 R In an exclusive and separated building? 8.6.4.2.2 I In exclusive and separated areas?

8.6.4.3 I

If there is an exclusive area, is the air insufflating and exhausting system independent from the ones present in the other areas or premises?

8.6.4.4 N Does the air exhaustion system have devices to avoid the environment contamination?

8.6.4.5 N Do the employees wear individual protection equipment during all the production process?

8.6.4.6 N Are periodical specific medical exams performed on people handling penicillin products?

8.6.4.6.1 N Are there records?

8.6.4.7 R Are periodical changing shifts performed among the production area employees?

8.6.4.7.1 INF What is the periodicity? __________________________ 8.6.4.7.2 N Are there records?

8.6.4.8 N Does the Validation Master Plan include all the steps of process of the production of penicillin products?

8.6.4.8.1 N Are there approved protocols to the ongoing validations?

8.6.4.9 What kind of validation is expected: 8.6.4.9.1 INF Prospective? 8.6.4.9.1.1 INF How many batches will be evaluated? 8.6.4.9.2 INF Retrospective? 8.6.4.9.2.1 INF How many batches will be considered? __________________________

8.6.4.9.2.2 N

Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.6.4.9.3 INF Concurrent? 8.6.4.9.3.1 INF How many batches will be evaluated?

8.6.4.10 N Do the tests results meet the criteria established in the approved protocol?

8.6.4.11 N Were the deviations found in relation to the established parameters in the approved protocol duly investigated?

8.6.4.12 N Is there a pre-established frequency to the periodical revalidation?

8.6.4.12.1 INF Which one? _____________________

8.6.4.12.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.6.5.- Cephalosporin products No. Qualif. Items YES NO N/A

8.6.5.1 INF Specify the pharmaceutical presentations produced: 8.6.5.2 The production of cephalosporin products is performed:

8.6.5.2.1 R In an exclusive and separated building?

8.6.5.2.2 I In exclusive and separated areas?

8.6.5.3 I

If there is an exclusive area, is the air insufflating and exhausting system independent from the ones present in the other areas or premises?

8.6.5.4 N Does the air exhaustion system have devices to avoid the environment contamination?

8.6.5.5 N Do the employees wear individual protection equipment during all the production process?

8.6.5.6 N Are periodical specific medical exams performed on people handling penicillin products?

8.6.5.6.1 N Are there records?

8.6.5.7 R Are periodical changing shifts performed among the production area employees?

8.6.5.7.1 INF What is the periodicity? __________________________ 8.6.5.7.2 N Are there records?

8.6.5.8 N Does the Validation Master Plan include all the steps of process of the production of penicillin products?

8.6.5.8.1 N Are there approved protocols to the ongoing validations? 7

8.6.5.9 What kind of validation is expected: 8.6.5.9.1 INF Prospective? 8.6.5.9.1.1 INF How many batches will be evaluated? 8.6.5.9.2 INF Retrospective?

8.6.5.9.2.1 INF How many batches will be considered? __________________________

8.6.5.9.2.2 N

Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.6.5.9.3 INF Concurrent? 8.6.5.9.3.1 INF How many batches will be evaluated?

8.6.5.10 N Do the tests results meet the criteria established in the approved protocol?

8.6.5.11 N Were the deviations found in relation to the established parameters in the approved protocol duly investigated?

8.6.5.12 N Is there a pre-established frequency to the periodical revalidation?

8.6.5.12.1 INF Which one? _____________________

8.6.5.12.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.6.6.- Cytostatic products No. Qualif. Items YES NO N/A

8.6.6.1 INF Specify the pharmaceutical presentations produced: _________________

8.6.6.2 N Is there an exclusive and separated area to the production of cytostatic products?

8.6.6.3 I Is the production of these products performed avoiding cross-contamination?

8.6.6.4 I Is the air insufflating and exhausting system independent from the other ones present in the other areas or premises?

8.6.6.5 N Does the air exhaustion system have devices to avoid the environment contamination?

8.6.6.6 N Do the employees wear individual protection equipment during all the production process?

8.6.6.7 N Are periodical specific medical exams performed on people handling the cytostatic substances?

8.6.6.7.1 N Are there records?

8.6.6.8 R Are periodical shifts performed among the employees of the production area?

8.6.6.8.1 INF What is the periodicity? 8.6.6.8.2 N Are there records?

8.6.6.9 N Does the Validation Master Plan include all the steps of the process of cytostatics production?

8.6.6.9.1 N Are there approved protocols to the ongoing validations?

8.6.6.10 What kind of validation is expected? 8.6.6.10.1 INF Prospective? 8.6.6.10.1.1 INF How many batches will be evaluated? 8.6.6.10.2 INF Retrospective?

8.6.6.10.2.1 INF How many batches will be considered? __________________________

8.6.6.10.2.2 N

Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.6.6.10.3 INF Concurrent? 8.6.6.10.3.1 INF How many batches will be evaluated?

8.6.6.11 N Do the tests results meet the criteria established in the approved protocol?

8.6.6.12 N Were the deviations found in relation to the established parameters in the approved protocol duly investigated?

8.6.6.13 N Is there a pre-established frequency to the periodical revalidation?

8.6.6.13.1 INF Which one? _____________________

8.6.6.13.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.7.- STERILE PRODUCTS 8.7.1 - Specific Conditions

No. Qualif. Items YES NO N/A 8.7.1.1 Is there a clean area for:

8.7.1.1.1 I Preparation of products with final sterilization or sterilizing filtration?

8.7.1.1.2 I Aseptic preparation of products without final sterilization?

8.7.1.1.3 I Filling of products with final sterilization?

8.7.1.1.4 I Aseptic filling of products without final sterilization?

8.7.1.1.5 N Manufacturing of plastic containers by lamination for SPGV [Large Volume Parenteral Solution]?

8.7.1.2 Is there an area for:

8.7.1.2.1 N Washing and sterilization/depyrogenization of vials and/or vial-flasks?

8.7.1.2.2 N Final sterilization of products? 8.7.1.2.3 N Visual inspection of filled products?

8.7.1.3 N

Does the design of the production areas make the effective cleaning and maintenance possible reducing the introduction, generation and retention of contaminants inside?

8.7.1.4 N Are the junctures among the floor, walls and ceiling free from angles?

8.7.1.5 N Are the walls, ceiling and floor sanitized?

8.7.1.5.1 N Are there records?

8.7.1.6 N Are the windows or viewers perfectly sealed?

8.7.1.7 I Is there a procedure to regulate the entrance of persons in the sterile products production area?

8.7.1.8 N Are the vials, vial-flasks, caps and tools transferred to the filling areas duly sterilized and/or depyrogenized?

8.7.2.- Washing, sterilization and depyrogenization area for containers and materials No. Qualif. Items YES NO N/A

8.7.2.1 N Is the area occupied appropriate to the operations volume?

8.7.2.2 N Is the circulation area free? 8.7.2.3 N Is the place clean? 8.7.2.4 R Is the area classified?

8.7.2.4.1 INF What is the classification of this area? __________________________

8.7.2.4.2 N Are there records?

8.7.2.5 INF Does the area have air filtration installations?

8.7.2.5.1 N Are there records of the filtered air controls?

8.7.2.6 N Are all the equipment identified?

8.7.2.7 N

Do all the equipment in use in the preparation of a product batch have tags identifying the in-process product and the batch number?

8.7.2.8 N Is the water used in the last rinse of the vials and vial-flasks of injection grade?

8.7.2.9 N

Is there some kind of filter in the water and compressed air systems which supplies the vials and vial-flasks washing equipment?

8.7.2.9.1 INF Types of filters ___________________________

8.7.2.9.2 N Are there records on the filters exchange?

8.7.2.10 The washing procedure of the vials and vial-flasks is: 8.7.2.10.1 INF Automatic? 8.7.2.10.2 INF Semi-automatic? 8.7.2.10.3 INF Manual?

8.7.2.11 INF Are the washed vials and vial-flasks packaged into metallic boxes?

8.7.2.12 N Is there a sterilization and depyrogenization oven?

8.7.2.12.1 INF Is the sterilization and depyrogenization oven a double-door one?

8.7.2.12.1.1 N If there is none, are the sterilized and depyrogenized vials and vial-flasks transferred to the filling area safely?

8.7.2.13 N Is there a sterilization and depyrogenization tunnel?

8.7.2.14 INF

Is the automatic washing machine of vials and vial-flasks connected to the sterilization and depyrogenization tunnel?

8.7.2.15 N Do the sterilization and depyrogenization equipment have recorders of time and temperature?

8.7.2.15.1 N Are there records?

8.7.2.16 N Are there sterilization autoclaves in the area?

8.7.2.16.1 INF Are the autoclaves double-door ones?

8.7.2.16.1.1 N If there is none, are the materials sterilized by humid heat transferred to the filling area safely?

8.7.2.17 N Does the humid heat sterilizer have time and temperature recorders?

8.7.2.17.1 N Are there records?

8.7.2.18 N Are indicators which might identify if the product was subjected to the sterilization process used?

8.7.2.19 N Are the sterilized materials identified?

8.7.2.20 N Are the equipment measuring instruments calibrated?

8.7.2.20.1 N Are there records?

8.7.2.21 N Is the sterilization by humid heat process validated?

8.7.2.22 N Is there an approved protocol to the validation of the sterilization process of materials by humid heat?

8.7.2.23 N Were three (3) consecutive satisfactory runs presented for each approved protocol?

8.7.2.24 N Is there a standardized diagram of the minimum and maximum materials load?

8.7.2.24.1 N Were established sterilization control parameters for each standardized load?

8.7.2.25 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.7.2.26 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.7.2.27 N Is the periodical revalidation foreseen?

8.7.2.27.1 N What is the frequency? ______________________________________

8.7.2.27.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.7.2.28 N Is the sterilization process by dry heat validated?

8.7.2.29 N Is there an approved protocol to the validation of the sterilization process by dry heat?

8.7.2.29.1 INF Were three (3) consecutive satisfactory runs presented for each approved protocol?

8.7.2.29.2 N Is there a standardized diagram of the minimum and maximum materials load?

8.7.2.30 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.7.2.31 N Were established sterilization control parameters for each standardized load?

8.7.2.32 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.7.2.33 N Is the periodical revalidation foreseen?

8.7.2.33.1 INF What is the frequency? ______________________________________

8.7.2.33.2 N Are the results obtained in the periodical revalidation in accordance with the approved protocol?

8.7.2.34 N Is the depyrogenization process validated?

8.7.2.34.1 INF Were three (3) consecutive satisfactory runs presented for each approved protocol?

8.7.2.36 N Is there a standardized diagram of the minimum and maximum products/materials load?

8.7.2.36.1 N Were established sterilization control parameters for each standardized load?

8.7.2.37 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.7.2.38 N Is the periodical revalidation foreseen?

8.7.2.38.1 INF Which one? _____________________________________________

8.7.2.39 INF In case of the use of plastic bottles, what is the method employed? _______

8.7.2.39.1 N Are there records?

8.7.2.40 INF Does the company use the sterilization process by ethylene oxide?

8.7.2.40.1 INF In what kinds of components? 8.7.3.- Area for the preparation of products with final sterilization or with sterilizing filtration

No. Qualif. Items YES NO N/A

8.7.3.1 N Is the preparation clean area appropriate for the operations volume?

8.7.3.2 The preparation of sterile products is performed: 8.7.3.2.1 INF Open system?

8.7.3.2.1.1 N Are the sterile products prepared in a grade C clean area (class 10,000)?

8.7.3.2.2 INF Closed system?

8.7.3.2.2.1 N Are the solutions prepared in a grade D clean area (class 100,000)?

8.7.3.3 N Does the area have a positive pressure in comparison to the appended areas?

8.7.3.4 N Is there an antechamber to the entrance of personnel in the area of preparation of sterile products?

8.7.3.5 N Is there an antechamber to the entrance of materials in the area of preparation of sterile products?

8.7.3.6 N Is there a pressure graduator from the sterile products preparation area to the antechambers and appended areas?

8.7.3.7 Are there records of:

8.7.3.7.1 N Differential pressure among different areas?

8.7.3.7.2 N Relative humidity of the areas?

8.7.3.7.3 N Environmental temperature of the areas?

8.7.3.7.4 N Are the registered values in accordance with the established in the SOP?

8.7.3.7.5 N Are the measuring instruments calibrated?

8.7.3.7.5.1 N Are there records? 8.7.3.8 Is the monitoring of particles performed: 8.7.3.8.1 N Viable? 8.7.3.8.2 N Non viable? 8.7.3.8.1 N Are there records?

8.7.3.9 N Are microbiological controls of the surfaces performed?

8.7.3.9.1 N Are there records?

8.7.3.10 N In case of deviations in relation to the limits established is an investigation performed to evaluate the causes?

8.7.3.10.1 N Are preventive and/or corrective actions taken in relation to the identified causes?

8.7.3.10.2 N Are there records?

8.7.3.11 N Are the garment and personal hygiene procedures for this area fulfilled?

8.7.3.11.2 N Are the uniforms worn in the grade C area sterilized?

8.7.3.11.3 N Is the fabric used in the uniforms from a material that avoids the loose of fibers or particles?

8.7.3.12 N Are the gloves free from lubricants which release particles?

8.7.3.13 N

Is there a procedure defining the entrance conditions of raw materials, materials and equipment in the clean area of preparation?

8.7.3.14 N Are all the sterile products preparation operations registered and signed by their performer?

8.7.3.14.1 N Are all the production critical steps signed by the indicated supervisor?

8.7.3.15 N Are all the equipment used in the production of a sterile product batch identified?

8.7.3.16 If there are measuring scales and containers in the preparation area of sterile products, are they:

8.7.3.16.1 N Regularly calibrated? 8.7.3.16.1.1 N Are there records? 8.7.3.16.2 N Regularly checked? 8.7.3.16.2.1 N Are there records?

8.7.3.16.3 N Are the verifications done with duly regulated standard weights?

8.7.3.17 N

Is there an appropriate separation between the equipment in order to avoid mixings or cross-contamination when batches of different products are simultaneously produced?

8.7.3.18 I Is water for injection used in the sterile products preparation?

8.7.3.18.1 N Is the water for injection released by the Quality Control before being used?

8.7.3.19 R Are the reactor sterilized by pure steam?

8.7.3.20 N Are in-process controls performed?

8.7.3.20.1 INF Which ones? ______________________________________________

8.7.3.20.2 N Are there records?

8.7.3.21 N Is the pipes used to transfer a solution or suspension to the filling area sanitized/sterilized?

8.7.3.22 INF Is the solution filtered through an sterilizing filter?

8.7.3.23 N Are tests to determine the integrity of the sterilizing filter performed?

8.7.3.23.1 N Are there records?

8.7.3.24 N

After used, are all the tools, equipment and containers thoroughly washed, and if required, sterilized and kept this way until the next use?

8.7.3.25 N Are they identified with tags certifying this condition?

8.7.4. Filling area of products with final sterilization

No. Qualif. Items YES NO N/A

8.7.4.1 N Is the clean area of final sterilization products filling appropriate to the operations volume?

8.7.4.2 N Is the clean area of final sterilization products filling of grade C (class 10,000)?

8.7.4.3 N Does the area have a positive pressure in comparison to the appended areas?

8.7.4.4 N Is there an antechamber to the entrance of personnel in the sterile products filling area?

8.7.4.5 N Is there an antechamber to the entrance of materials in the sterile products filling area?

8.7.4.6 N Is there a pressure graduator of the sterile products to the antechambers and the appended areas?

8.7.4.7 Are there records of:

8.7.4.7.1 N Differential pressure among different areas?

8.7.4.7.2 N Relative humidity of the area?

8.7.4.7.3 N Environmental temperature of the area?

8.7.4.7.4 N Are the values registered in accordance with the established in the SOP?

8.7.4.8 N Are the measuring instruments regulated?

8.7.4.8.1 N Are there records? 8.7.4.9 The monitoring of particles is performed: 8.7.4.9.1 N Viables 8.7.4.9.2 N Non-viables 8.7.4.9.3 N Are there records?

8.7.4.10 N In case of deviations in relation to the limits established is an investigation performed to evaluate the causes?

8.7.4.11 N Are preventive and/or corrective actions taken in relation to the identified causes?

8.7.4.11.1 N Are there records?

8.7.4.12 N Are the garments and personal hygiene procedures fulfilled for this area?

8.7.4.13 I Are the uniforms worn in the clean area of parenteral solutions filling sterilized?

8.7.4.13.1 N Is the fabric used in the uniforms of a material that avoid the loose of fibers and particles?

8.7.4.14 N Are the gloves free from lubricants which release particles?

8.7.4.15 N

Is there a procedure to define the entry conditions of raw materials, materials and equipment in the clean area of the parenteral solutions filling?

8.7.4.16 N

Are the vials, vial-flasks, caps and tools which are transferred to the final sterilization product filling area duly sterilized?

8.7.4.17 I Are the Production Order instructions accurately followed?

8.7.4.18 N Are all the filling operations registered and signed by their performer?

8.7.4.19 N

Is there an appropriate separation between the equipment to avoid mixings and cross-contamination when different products batches are simultaneously filled?

8.7.4.20 N Are all the equipment used in the sterile products filling identified?

8.7.4.21 The filling procedure of sterile products with final sterilization is: 8.7.4.21.1 INF Automatic? 8.7.4.21.2 INF Semi-automatic? 8.7.4.21.3 INF Manual?

8.7.4.22 N Is the filling of parenteral solutions performed under a grade A laminar flow (class 100)?

8.7.4.22.1 N Is the class A laminar flow certified? 8.7.4.22.2 N Are there records?

8.7.4.23 N Are frequent controls on volume/weight of filling performed?

8.7.4.23.1 N Are there records?

8.7.4.24 N Is there a system to identify the sterilized products?

8.7.4.25 N Is the sterile products filling area qualified?

8.7.4.25.1 N Are there records?

8.7.4.26 N

Is the filling of sterile ointments, creams, suspension, and emulsions with final sterilization performed in a grade C environment(class 10,000)?

8.7.4.27 N Does the Validation Master Plan include the filling of sterile ointments, creams, suspensions and emulsions?

8.7.4.28 N Are there approved protocols to the ongoing validations?

8.7.4.29 What kind of validation is expected: 8.7.4.29.1 INF Prospective?

8.7.4.29.1.1 INF How many batches will be evaluated? ____________________________

8.7.4.29.2 INF Retrospective?

8.7.4.29.2.1 INF How many batches will be considered? __________________________

8.7.4.29.2.2 N

Were all the batches considered in the Retrospective Validation produced according to the same operational parameters and specifications?

8.7.4.29.3 INF Concurrent?

8.7.4.29.3.1 INF How many batches will be considered? _________________________

8.7.4.30 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.7.4.31 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.7.4.32 N Is there a pre-established frequency for the periodical revalidation?

8.7.4.32.1 INF Which one? ___________________________________________

8.7.4.32.2 N Are the results obtained from the periodical revalidation in accordance with the approved protocol?

8.7.5 Products final sterilization area No. Qualif. Items YES NO N/A

8.7.5.1 R Is there a specific area to the final sterilization of products?

8.7.5.2 N Are individual protection equipment worn?

8.7.5.3 R Is there an exhaustion system? 8.7.5.4 N Are the autoclaves identified?

8.7.5.5 N Are there sterilization temperature records?

8.7.5.6 N Are there sterilization time records?

8.7.5.7 N Are biological indicators used to manage the sterilization process?

8.7.5.7.1 N Are there records?

8.7.5.8 R After autoclavage, is any air-tightness test performed in the sterilized containers?

8.7.5.9 N Are the sterilization records annexed to the Production Order?

8.7.5.10 N Are there safe procedures to avoid the mixing of non-sterilized products from the already sterilized ones?

8.7.5.11 N Are the sterilized products identified as such?

8.7.5.12 N

Are the recipients containing the sterilized products well closed and identified in accordance to their contents?

8.7.5.13 N Is the final sterilization of products process validated?

8.7.5.14 N Is there an approved protocol to the validation of the products of final sterilization process?

8.7.5.14.1 N Were three (3) consecutive satisfactory runs presented for each approved protocol?

8.7.5.15 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.7.5.16 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.7.2.17 N Is the periodical revalidation foreseen?

8.7.5.17.1 INF What is the frequency? _________________________________

8.7.5.17.2 N Are the results obtained from the periodical revalidation in accordance with the approved protocol?

8.7.6.- Aseptic preparation area No. Qualif. Items YES NO N/A

8.7.6.1 I Is there a clean area for the aseptic preparation of products with final sterilization?

8.7.6.2 N Is the clean area for the aseptic preparation appropriate for the operations volume?

8.7.6.3 N Are the sterile products prepared in a grade B (class 100) or C (class 10,000) area?

8.7.6.4 N Does the area have a positive pressure in comparison to the other appended areas?

8.7.6.5 N Is there and antechamber to the entrance of personnel in the sterile products preparation area?

8.7.6.6 N Is there an antechamber for the entrance of materials in the aseptic preparation of sterile products?

8.7.6.7 N Is there a pressure graduator of the aseptic preparation area to the antechambers and appended areas?

8.7.6.8 Are there records of:

8.7.6.8.1 N Differential pressure among the different areas?

8.7.6.8.2 N Relative humidity of the areas?

8.7.6.8.3 N Environmental temperature of the areas?

8.7.6.8.4 N Are the registered values in accordance with the established SOP?

8.7.6.9 The monitoring of particles is performed: 8.7.6.9.1 N Viable 8.7.6.9.2 N Non-viable 8.7.6.9.2.1 N Are there records?

8.7.6.10 N In case of deviations in relation to the limits established is an investigation performed to evaluate the causes?

8.7.6.11 N Are preventive and/or corrective actions taken in relation to the identified causes?

8.7.6.11.1 N Are there records?

8.7.6.12 N Are the garment and personal hygiene procedures for this area fulfilled?

8.7.6.12.1 N Are the uniforms worn in accordance with the clean area cleaning grade?

8.7.6.12.2 I Are the uniformed worn in the grade B or C area sterilized?

8.7.6.12.3 N Is the fabric used in the uniforms made of a material that avoid the loose of fibers or particles?

8.7.6.13 N Are the gloves free from lubricants which release particles?

8.7.6.14 N

Is there a procedure to define the entrance conditions of raw materials, materials and equipment in the aseptic preparation area?

8.7.6.14.1 N Are there records?

8.7.6.15 N

Are all the aseptic preparation operations of sterile products registered and signed by their performer?

8.7.6.16 N Are all the containers used in the aseptic preparation of a product batch identified?

8.7.6.17 N Are all the equipment used in the preparation of a product batch identified?

8.7.6.18 N

Is there an appropriate separation between the equipment to avoid mixings and cross-contamination when different products batches are simultaneously produced?

8.7.6.19 I Is water for injection used in the aseptic preparation of sterile products?

8.7.6.19.1 N Is the water for injection released by the Quality Control before use?

8.7.6.20 I Are the reactors sterilized with pure steam?

8.7.6.21 I Are the tools entering the aseptic area sterilized?

8.7.6.22 I Is the products handled under a grade A laminar flow (class 100)?

8.7.6.22.1 N Is the laminar flow qualified? 8.7.6.22.2 N Are there records? 8.7.6.23 N Are in-process controls performed?

8.7.6.23.1 INF Which ones? ____________________________________________

8.7.6.23.2 N Are there records?

8.7.6.24 INF Is the solution filtered through a sterilizing filter?

8.7.6.24.1 INF What is the sterilizing filter size [pore size]? ____________µ

8.7.6.24.2 N Are tests to determine the integrity of the sterilizing filter performed?

8.7.6.24.3 N Are there records?

8.7.6.25 N

After use, are all the tools, equipment and containers thoroughly washed/sterilized and kept this way until the next use?

8.7.6.26 N Are they identified with tags certifying this status?

8.7.7 Products aseptic filling area (sterile raw materials or products with sterilizing filtration) No. Qualif. Items YES NO N/A

8.7.7.1 N Is the sterile products filling clean area a grade B (class 100) or C (class 10,000)?

8.7.7.2 N Does the area have a positive pressure in comparison to the appended areas?

8.7.7.3 N Is there an antechamber for the entrance of personnel in the sterile products filling area?

8.7.7.4 N Is there and antechamber to the entrance of materials in the sterile products filling area?

8.7.7.5 N Is there a pressure graduator of the aseptic preparation area to the antechambers and appended areas?

8.7.7.6 Are there records of:

8.7.7.6.1 N Differential pressure among the different areas?

8.7.7.6.2 N Air relative humidity?

8.7.7.6.3 N Environmental temperature of the area?

8.7.7.6.4 N Are the values registered in accordance with the established in the SOP?

8.7.7.7 The monitoring of particles is performed: 8.7.7.7.1 N Viable? 8.7.7.7.2 N Non-viable? 8.7.7.7.3 N Are there records?

8.7.7.8 N Are microbiological controls on the surface performed?

8.7.7.8.1 N Are there records?

8.7.7.9 N In case of deviations in relation to the limits established is an investigation performed to evaluate the cause?

8.7.7.10 N Are preventive and/or corrective actions taken in relation to the identified causes?

8.7.7.10.1 N Are there records?

8.7.7.11 N Are the garments and personal hygiene procedures fulfilled for this area?

8.7.7.12 N Are the uniforms worn in accordance with the cleaning grade of the clean area?

8.7.7.13 I Are the uniforms worn in the clean area of aseptic filling sterilized?

8.7.7.13.1 N Is the fabric used in the uniform made from a material that avoids the loose of fibers or particles?

8.7.7.14 N Are the sterile gloves free from lubricants which release particles?

8.7.7.15 N

Is there a procedure to define the entrance conditions of raw materials, materials and equipment into the clean area of aseptic filling of products without final sterilization?

8.7.7.15.1 N Are there records?

8.7.7.16 N

Are the vials, vial-flasks, caps and tools entering the clean area of aseptic filling duly sterilized and/or depyrogenized?

8.7.7.17 N Are all the aseptic filling operations registered and signed by their performer?

8.7.7.18 N

Is there a physical separation appropriate between the equipment to avoid mixings or cross-contamination when different products batches are simultaneously filled?

8.7.7.19 N Are all the equipment used in the aseptic filling of sterile products identified?

8.7.7.20 The procedure of aseptic filling of sterile products is: 8.7.7.20.1 INF Automatic? 8.7.7.20.2 INF Semi-automatic? 8.7.7.20.3 INF Manual?

8.7.7.21 N The product filling is performed under a grade A laminar flow (class 100)?

8.7.7.21.1 N Is the class A laminar flow qualified? 8.7.7.21.2 N Are there records?

8.7.7.22 N Are in-process volume/weight controls of the products filled performed?

8.7.7.22.1 N Are there records?

8.7.7.23 N Are the recipients containing bulk products identified?

8.7.7.24 N Is the aseptic filling of the product validated?

8.7.7.25 N Is a simulated filling performed with the mean of culture?

8.7.7.26 N Is there an approved protocol to the validation of the process of aseptic filling of products?

8.7.7.26.1 N Were three (3) consecutive satisfactory runs presented for each approved protocol?

8.7.7.27 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.7.7.28 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.7.7.29 N Is a periodical revalidation foreseen?

8.7.7.29.1 INF What is the frequency? _______________________________________

8.7.7.30 N Are the results obtained from the periodical revalidation in accordance with the approved protocol?

8.7.7.31 INF Is the filled products lyophilized?

8.7.7.32 N Is the lyophilizer installed in the aseptic filling area?

8.7.7.33 N

Is the transfer of the containers with the product to the lyophilizer performed under a class A laminar flow?

8.7.7.34 N Are the temperature, time and air-tightness parameters monitored during the lyophilization process?

8.7.7.34.1 N Are there records?

8.7.7.34.2 N Are the records annexed to the Production Order?

8.7.7.35 N Is the lyophilization process validated?

8.7.7.36 N Is there an approved protocol to the validation of the lyophilization process?

8.7.7.37 N Were three (3) consecutive satisfactory runs presented for each approved protocol?

8.7.7.38 N Do the tests results meet the acceptance criteria established in the approved protocol?

8.7.7.39 N Were the deviations found in relation to the parameters established in the approved protocol duly investigated?

8.7.7.40 N Is a periodical revalidation foreseen? 8.7.7.40.1 INF What is the frequency? _____________________________

8.7.7.41 N Are the results obtained from the periodical revalidation in accordance with the approved protocol?

8.7.7.42 N Is the re-riveting performed under a class C laminar flow?

8.7.8- Filled product inspection area No. Qualif. Items YES NO N/A

8.7.8.1 N Is there a separated place to the visual inspection of the filled products?

8.7.8.2 R Is the occupied area appropriate to the operations volume?

8.7.8.3 N Are individual protection equipment worn?

8.7.8.4 R Is there the need to control temperature and humidity in the visual revision area to certain products?

8.7.8.5 R Are there equipment to control the area temperature and humidity?

8.7.8.6 N Are there records?

8.7.8.7 R Are there records on the cleaning and disinfection procedures?

8.7.8.8 N Was the area inspected to check the presence of previously inspected products?

8.7.8.8.1 N Are there records?

8.7.8.9 N

Is there a separation between the visual inspection lines when different product batches are simultaneously inspected?

8.7.8.10 N Are the recipient containing the products identified in accordance with their contents?

8.7.8.11 INF Is the inspection performed by automatic equipment?

8.7.8.11.1 N Is the equipment periodically calibrated?

8.7.8.11.2 N Are there records? 8.7.8.12 INF Is the visual inspection manual?

8.7.8.12.1 N Is the visual inspection performed against a clear or dark background?

8.7.8.12.2 N Are the inspectors subjected to regular ophthalmologic examinations?

8.7.8.12.3 INF What is the periodicity? ______________________________________

8.7.8.12.4 N Are there records?

8.7.8.13 N Are periodical resting stops of inspectors maintained?

8.7.8.13.1 INF How long does the inspector remains in the revisions operation? ______hours

8.7.8.13.2 INF How long is the inspectors resting stop?_____________ minutes

8.7.8.14 N Are there records of products disposal in the visual inspection process?

8.7.9.- Packaging 8.7.9.1- Secondary packaging area

No. Qualif. Items YES NO N/A

8.7.9.1.1 N Is there an area to the secondary packaging operations?

8.7.9.1.2 Is the secondary packaging area: 8.7.9.1.2.1 INF By production line?

8.7.9.1.2.2 INF Common to all of the products manufactured in the company?

8.7.9.1.3 N Is the area clean?

8.7.9.1.4 INF Is there a place that required controlled environmental conditions?

8.7.9.1.5 If required, are there equipment to control: 8.7.9.1.5.1 N Temperature? 8.7.9.1.5.2 N Are there records?

8.7.9.1.6 I Is the secondary packaging operation performed according to the Production Order/Packaging Order?

8.7.9.1.7 N Are all the packaging operations registered and signed by their performer?

8.7.9.1.8 N Are all the recipients containing the filled product duly identified in accordance with their content?

8.7.9.1.9 N Is the secondary packaging line identified in accordance with the product batch to be packaged?

8.7.9.1.10 N Is there an appropriate separation between the equipment when different product batches are simultaneously packaged?

8.7.9.1.11 N Are in-process controls performed during the secondary packaging operation?

8.7.9.1.11.1 INF Which ones? 8.7.9.1.11.2 N Are there records?

8.7.9.1.13 N After the packaging, do the products remain in quarantine?

8.7.9.1.13.1 N Are there records?

8.7.9.1.14 N Is the reconciliation among the theoretical quantity of printed, filling materials and bulk product and the actual quantity used?

8.7.9.1.14.1 N Are there records? 8.7.9.2. Labeling

No. Qualif. Items YES NO N/A

8.7.9.2.1 I Is the access to the labels, in the packaging area, allowed only to duly authorized persons?

8.7.9.2.2 N

Are the packaging lines inspected, in order to verify if they correspond to the product to be labeled and to the conformity with the Production Order/Packaging Order/ before use?

8.7.9.2.3 N

Are the labeling machines inspected, before use, in relation to the absence of printed materials from previous products?

8.7.9.2.4 I Are the unused labels printed with the batch number and the expiration date destroyed?

8.7.9.2.4.1 N Are there records?

8.7.9.2.5 N

Are the quantities of labels received, used, including the damaged ones and the destroyed ones, registered?

8.7.9.2.6 N

Are all the differences between the number of received labels, used labels, including the damaged and destroyed ones, investigated?

8.7.9.2.6.1 N Are there records?

8.7.9.2.7 R Are the labels unprinted with the batch number and the expiration date returned to the warehouse?

8.7.9.2.7.1 N Is there a person responsible for this return?

8.7.9.2.7.2 N Are there records? 9. QUALITY CONTROL 9.1. General Conditions

No. Qualif. Items YES NO N/A

9.1.1 I Is the Quality Control independent from the production?

9.1.2 N Are the Quality Control areas consistent with the operations volume?

9.1.3 N Are the areas clean? 9.1.4 N Do the personnel wear uniforms?

9.1.5 N Are the uniforms clean and in good preservation status?

9.1.6 INF Are there drains in the area? 9.1.6.1 N If yes, are they siphoned?

9.1.7 N Are there records on the cleaning and disinfection procedures?

9.1.8 N Is the illumination appropriate?

9.1.9 INF What is the professional background of the person responsible for the Quality Control? ________________________________________________

9.1.10 INF To whom is the responsible for the Quality Control subjected to? __________

9.1.11 R Does the company have defined qualification criteria for the main personnel in the Quality Control?

9.1.12 R Is there a training program ensuring the performance of the employees in the laboratory activities?

9.1.12.1 N Are there records?

9.1.13 INF Are there essays performed by hired laboratories?

9.1.13.1 INF What essays? ______________________________ 9.1.13.2 INF What laboratories?______________________________

9.1.14 N

Are there written specifications to all the raw materials, packaging materials, intermediary, bulk and finished products?

9.1.15 N Are the SOPs related to the activities of each area available in the respective working places?

9.1.16 Are there sampling plans defined for: 9.1.16.1 N Raw materials? 9.1.16.2 N Packaging materials? 9.1.16.3 N Intermediary products? 9.1.16.4 N Bulk products? 9.1.16.5 N Finished products? 9.1.17 Is the Quality Control responsible for the analysis of: 9.1.17.1 I Raw materials? 9.1.17.2 I Packaging materials? 9.1.17.3 I Intermediary products? 9.1.17.4 I Bulk products? 9.1.17.5 I Finished products?

9.1.18 R Are there designees to supervise the performance and evaluate the results of the tests performed?

9.1.19 N

Is the Quality Control responsible for the performance of analytical essays of products manufactured upon the contract of third parties?

9.1.20 N

Is there an authorized person to evaluate the analysis report issued by the third party as for the product release?

9.1.21 I Does the Quality Control keep records on the analyses performed?

9.1.22 Are reference samples kept in quantities sufficient to perform the quality control tests, if required:

9.1.22.1 I Raw materials? 9.1.22.2 I Finished product?

9.1.23 N Is the retention period of these samples defined?

9.1.24 R Are the finished products samples, when possible, kept in their final package?

9.1.25 R Are there procedures for the raw material re-analysis respecting the expiration date established by the manufacturer?

9.1.25.1 N Are there records?

9.1.26 N Are there operation procedures of the equipment used by the Quality Control?

9.1.27 The Quality Control equipment/instruments have procedures of:

9.1.27.1 N Preventive maintenance of equipment and instruments?

9.1.27.1.1 N Are there records? 9.1.27.2 N Equipment and instruments use? 9.1.27.2.1 N Are there records?

9.1.27.3 N Equipment and instruments calibration?

9.1.27.3.1 N Are there records?

9.1.28 I

Does the quality control verify if each product batch produced meets the established specifications, before being released?

9.2. Physical-chemical quality control No. Qualif. Items YES NO N/A

9.2.1 N Are the Laboratory premises appropriate for the work volume?

9.2.2 N

Are the procedures related to the analytical methods referred to and followed for the analyses performance?

9.2.3 N Is the distribution of equipment/instruments ordered and rational?

9.2.4 N Are there biosafety equipment, if required?

9.2.4.1 N Are they regularly checked/tested? 9.2.4.2 N Are there records? 9.2.5 N Are there reference standards? 9.2.5.1 INF Primary standards? 9.2.5.1.1 INF Origin: ___________________________________________ 9.2.5.2 INF Secondary standards?

9.2.5.2.1 INF Are they authorized against the primary standards?

9.2.5.2.2 INF Who certified? ______________________________________ 9.2.5.3 N Reference materials? 9.2.5.3.1 INF Origin: __________________________________________

9.2.5.4 N Does its preservation meet the recommendations established by the manufacturer?

9.2.5.5 The standards record presents the following information: 9.2.5.5.1 N Batch number? 9.2.5.5.2 N Strength/purity? 9.2.5.5.3 N Expiration date?

9.2.5.5.4 N Origin? 9.2.5.5.5 N Storage conditions?

9.2.5.6 N

Are the solutions prepared from reference standards identified with the following data: substance name, concentration, solvent (when it is not an aqueous solution), expiration date, storage conditions, precautions or special care (when applicable), restrictions to use, preparation date, identification of the technician responsible for the preparation?

9.2.5.7 I Are reference standards used in the identity and content tests, when required?

9.2.5.7.1 N Are there reference standards to identify and quantify impurities, when required?

9.2.5.7.2 N Are there reference standards to identify and quantify decomposing products, when applicable?

9.2.5.8 I Are there reference standards for all the active substances used by the company, when applicable?

9.2.6 I

Does the laboratory perform all the tests required in the technical specification of the manufactured products?

9.2.7 N

Are the equipment/instruments installed in accordance with the recommendations determined by their manufacturers?

9.2.7.1 R Is there an equipment to stabilize the electrical current?

9.2.7.2 N Is the operation manual of each equipment available in the laboratory?

9.2.8 N Are there procedures to the preparation of the reagent solutions used?

9.2.9 N

Are the recipients containing the reagent solutions identified with the following data: solution name, concentration, correction factor, precautions or special care (when applicable), expiration date, storage condition, preparation date, identification of the technician responsible for the preparation?

9.2.10 N Are the quality control essays methodologies validated according to the Validation Master Plan?

9.3. Microbiological quality control No. Qualif. Items YES NO N/A

9.3.1 N Are the Laboratory premises appropriate to the work volume?

9.3.2 N

Is there a defined cleaning program which takes into consideration the result of the environmental management and the contamination possibility?

9.3.2.1 N Are there records?

9.3.3 N Is the equipment distribution ordered and rational?

9.3.4.1 N Are there biosafety equipment, when required?

9.3.4.1.1 N Are they regularly checked/tested? 9.3.4.1.2 N Are there records?

9.3.5 INF Is there an exclusive autoclave to the materials decontamination?

9.3.5.1 N

If not, is there a written procedure containing precautions to the separation of loads to sterilization and contaminated loads?

9.3.5.1.1 N Are there records?

9.3.6 N Is there a defined program to the internal cleaning and external environment of the autoclave?

9.3.6.1.1 N Are there records?

9.3.7 N

Were performance qualification studies conducted for each operational run and each type of load used in the autoclaves?

9.3.7.1 N Are there records?

9.3.8 N

Does the Validation Master Plan include the qualification of heat ovens, incubators, water-baths and clean rooms with controlled temperature?

9.3.9 INF Are microbiological tests performed in the raw materials?

9.3.9.1 N Are there records?

9.3.10 Microbiological tests are performed to determine viable particles:

9.3.10.1 N In the clean areas of sterile products production?

9.3.10.2 N In the production areas of non-sterile products?

9.3.10.3 N In the sterility tests rooms? 9.3.10.4 N Are there records?

9.3.10.5 N Are there alert limits and action limits established to the determination of viable particles?

9.3.11 Surface microbiological tests are performed:

9.3.11.1 N In the clean areas of sterile products production?

9.3.11.2 N In the sterility tests rooms?

9.3.11.3 N Are there alert limits and action limits established to the surface microbiological tests?

9.3.11.3.1 N

In case of results above the established alert limits, is an investigation performed to evaluate the causes?

9.3.11.3.2 N Are immediate actions taken in case of results above the action limits?

9.3.11.3.3 N Are there records?

9.3.12 N Are sterility tests performed in sterile products?

9.3.12.1 N Are there records?

9.3.13 R Is the sterility test performed in clean water?

9.3.13.1 INF What is the area classification? _______________________________

9.3.13.2 INF Is there an antechamber?

9.3.13.3 N Are the floor, walls and ceiling in good preservation status?

9.3.13.4 N Are they covered with washable material?

9.3.14 The clean area have the control of: 9.3.14.1 INF Temperature? 9.3.14.2 INF Air relative humidity? 9.3.14.3 INF Differential pressure? 9.3.14.4 INF Particles monitoring?

9.3.15 N Are the sterility tests performed under a laminar flow?

9.3.15.1 INF Type of laminar flow? __________________________

9.3.15.2 N Is the laminar flow qualified? 9.3.16 The company uses:

9.3.16.1 INF Means of culture prepared by the laboratory itself?

9.3.16.2 INF Means of culture ready to use? 9.3.16.3 INF Both

9.3.17 N Is there a procedure for the preparation of the means of culture batches?

9.3.18 N

Is there a record on the means of culture batches preparation used in the sterility tests, containing at least one of the following data: name of the mean, batch number, expiration date?

9.3.19 The means of culture are controlled in relation to: 9.3.19.1 N Fertility? 9.3.19.2 N Sterility?

9.3.20 N

Are the reagent solutions (including the stock solutions), means, diluents, and other suspension fluids identified with the following data: name, concentration, expiration date and/or recommended storage periods, preparation date, identification of the technician responsible for the preparation?

9.3.21 INF Are there reference cultures acquired from acknowledged national or international sources?

9.3.22 N

Are there written procedures for the preparation and preservation of sub-cultures to be used as reference stock?

9.3.23 N

Are purity and biochemical tests performed, when required, in reference stocks and/or working cultured?

9.3.23.1 N Are there records?

9.3.24 N

Are there written procedures to the collection and handling of samples to avoid the material contamination?

9.3.25 N

Are there written procedures to the disposal of means of culture and dischargeable materials contaminated to avoid the environment and other materials contamination?

9.3.26 N Are endotoxin tests (LAL) or animal tests performed in the apyrogenic products?

9.3.26.1 INF Which is the methodology used? _______________

9.3.26.2 N Is the method valid?

9.3.27 N

Does the Validation Master Plan include the validation of the microbiological and biological essays used?

9.3.28 N

Is there a general protocol approved and an individual protocol to each method being validated according to the chronogram, taking into account the parameters to be tested, characteristics and number of tests to be performed, statistical evaluation of the results?

9.4. Biological quality control No. Qualif. Items YES NO N/A

9.4.1 N Is there an area separated from the other premises to perform the animal biological tests?

9.4.2 N Is the laboratory in satisfactory cleaning conditions?

9.4.3 INF What is the origin of the animals? ___________________________ 9.4.4 N Is the animals supplier qualified? 9.4.5 N Is there a quarantine place?

9.4.6 N Are controls performed for the liberation of the animals from quarantine?

9.4.6.1 N Are there records? 9.4.7 INF What are the biological tests performed: ________________________ 9.4.8 INF Are in vivo pyrogen tests performed?

9.4.8.1 N Is the rabbits temperature reading test performed automatically?

9.4.8.2 INF Are rectal probes used? 9.4.8.3 N Are the probes calibrated? 9.4.8.3.1 N Are there records? 9.4.9 N Are the test animals identified? 9.4.9.1 INF How? ____________________________________________________ 9.4.9.2 N Are there records?

9.4.10 INF What is the destination of the discharged animals _____________________

9.4.10.1 N Are there records?

9.4.11 N Are toxicity tests performed in plastic containers for SPGV [Large Volume Parenteral Solutions]?

10. QUALITY ASSURANCE No. Qualif. Items YES NO N/A

10.1 I Is there a Quality Assurance system in the company?

10.2 N Is this program released to all employees?

10.3 N Are the responsibilities for the Quality Assurance management clearly defined?

10.4 N Are there procedures for the release of the Good Manufacturing Practices fulfillment?

10.4.1 N Are these procedures followed?

10.5 N Is there a planning and chronogram of personnel training?

10.5.1 N Are there records on each employee training?

10.6 N

Are the employees trained and oriented to ensure the correct and complete performance of the defined processes and procedures?

10.7 N

Is the introduction of new knowledge in the processes, or enhancements, only implemented after the complete evaluation and approval by the Quality Assurance?

10.8 I Are self-inspections performed with the purpose of verifying the fulfillment of the Good Manufacturing Practices?

10.8.1 INF What is the frequency of the self-inspections? _______________________

10.8.2 N Are there records?

10.9 N Is there a formal system to the investigation on quality deviations?

10.9.1 N

Are there written procedures to the adoption of corrective and/or preventive measures after the identification of the quality deviations causes?

10.10 Is there a stability study program to: 10.10.1 N Products to be registered? 10.10.2 N Marketed products? 10.10.3 N Primary packaging material change?

10.11 N

Are the long term stability studies performed in conformity with the established conditions to Zone IV, according to the current legislation?

10.12 N

If the company imports bulk products, are there studies proving the stability and storage period in the packages used?

10.13 In case of imported products the stability study for Zone IV is conducted: 10.13.1 INF At the manufacturing site? 10.13.2 INF In Brazil? 10.13.3 N Were results presented? 10.14 Is there a weather controlled chamber to: 10.14.1 INF Accelerated studies? 10.14.2 INF Long term Zone IV studies?

10.14.3 N Do the weather controlled chambers have a record system of its operational conditions?

10.15 INF

Is there a follow-up system that allows to check if the storage conditions are being met, and if the product maintains its quality during its validity period?

10.15.1 N Are there records? 10.16 Is there a Validation Master Plan containing at least: 10.16.1 N Company validation policy?

10.16.2 N Description of the premises and procedures?

10.16.3 N Planning and chronogram of the activities?

10.16.4 N Responsibilities?

10.16.5 N Description of equipment, instruments, processes and systems to be validated?

10.16.6 N Reason to the inclusion or exclusion of a certain validation?

10.16.7 N Documents tracking system?

10.16.8 N Frequency of the periodical revalidation based on the process risk?

10.16.9 N Cross-reference to other documents? 10.16.10 N Specific training requirements? 10.17 Does the Validation Master Plan also include: 10.17.1 N Equipment Cleaning Validation? 10.17.2 N Analytical Methods Validation? 10.17.3 N Area cleaning? 10.17.4 N Sanitization, when applicable?

10.18 N

Are revalidations performed when changes which might affect the quality or reproducibility of a process or a control analytical method are introduced?

10.19 INF Is there a pharmacotechnical development laboratory in the company?

10.19.1 N

Are the pharmaceutical products designed and developed according to the Good Manufacturing Practices requirements?

10.20 Is the Quality Assurance sector responsible:

10.20.1 N For the approval of all the Standard Operation Procedures (SOPs) of the company?

10.20.2 N For keeping the original SOPs? 10.20.3 N For the distribution of SOPs? 10.20.4 N For the SOPs distribution control?

10.20.5 I For the evaluation of the documentation of the produced batches?

10.20.6 N For keeping the documentation of the produced batches?

10.21 I

Does the documentation of each batch produced allow the tracking of the materials and equipment used, procedures and quality controls performed?

10.21.1 INF What is the period established for the documentation to be kept? __________