Ispe Hvac Cop Anvisa Gmp Revisionpubliccomments

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National Health Surveillance Agency1

www.anvisa.gov.br 2

Public Consultation Nr. 3, dated January 13, 2009.3D.O.U [Federal Off icial Gazette] dated 02/17/09 4

The Collegiate Board of the National Health Surveillance Agency , pursuant to the powers5conferred upon it by paragraph IV of article 11 and of article 35 of the ANVISA Regulations, as approved by6Decree Nr. 3.029, dated April 16, 1999, and keeping in view the provisions laid down in paragraph V and in7§§ 1 and 3 of article 54 of the In-house Regulations, approved within the terms of Attachment I of Ordinance8Nr. 354 by ANVISA, dated August 11, 2006, republished in the DOU dated August 21, 2006, at a meeting9held on February 3, 2009,10

adopts the following Public Consultation and I, the Director President, order its publication:11

Article 1 It will remain open, counting from the date of publication of this Public Consultation, a term of 12sixty (60) days so that criticism and suggestions may be presented relative to the proposal of RDC-13Resolution on Good Manufacturing Practices for Medications, attached hereto.14

Article 2 Inform that the proposal of resolution will be available as a whole during the period of 15consultation at the following electronic address www.anvisa.gov.br and that suggestions must be forwarded16in writing to the following address: Agência Nacional de Vigilância Sanitária, SIA, Trecho 5, Área Especial 5717Cidade: Brasília - DF CEP: 71.205-050 or Fax: (061)3462-5702 or e-mail: [email protected] . 18

Article 3 At the end of the term stipulated in Article 1, the National Health Surveillance Agency will19work with the Bodies and Entities involved with the aim of consolidating the final text.20

DIRCEU RAPOSO DE MELLO 21

ATTACHMENT22

RDC RESOLUTION Nr. XXX, DATED XXXXXX XX, 2008 23

Provides for Good Manufacturing Practices for Medications24

The Collegiate Board of the National Health Surveillance Agency , pursuant to the powers25conferred upon it by paragraph IV of article 11 of the regulations approved by Decree Nr. 3.029, dated April2616, 1999, and keeping in view the provisions laid down in paragraph II and in §§ 1 and 3 of article 54 of the27In-house Regulations approved within the terms of Attachment I of Ordinance Nr. 354 by ANVISA, dated28August 11, 2006, republished in the DOU dated August 21, 2006, at a meeting held on December 18, 2006;29

whereas law Nr. 6.360, dated September 23, 1976;30

whereas Decree Nr. 79.094, dated January 5, 1977;31

whereas Law Nr. 9.782, dated January 26, 1999;32

whereas the need to update the Good Manufacturing Practices for Medications with the objective of 33following up the development of new technologies over the past few years and the relevance of national and34international documents with respect to the theme;35

whereas the recommendations by the World Health Organization (WHO) on the Certification of Quality36of Pharmaceutical Products, the object of international trade;37

whereas the need to standardize the actions of the Health Surveillance Agency; adopts the following38Resolution by the Collegiate Board and I, the Director President, order its publication:39

40

http://www.anvisa.gov.br/




mailto:[email protected]








41

Article 1 Order all medication manufacturing establishments to comply with the directives established42within the Good Manufacturing Practices for Medications Technical regulations, as well as with the43Attachments to the current Resolution.44

Article 2 RDC-Resolution Nr. 210 dated August 04, 2003 is hereby revoked.45

Article 3 A term of one year is granted for the conclusion of the computerized systems validation.46

Article 4 The updates to this Resolution, aiming at following up the development of new technologies47within the pharmaceutical sector, must be approved by the Collegiate Board of the National Health48Surveillance Agency, and published in the Federal Official Gazette.49

Article 5 The non-observance or disobedience of the provisions disclosed in this Resolution will50constitute a health violation, in the form of Law Nr. 6437, dated August 20, 1977, subjecting the violator to51the penalties provided for in this legal document.52

Article 6 This Resolution comes into effect on the date of its publication.53

DIRCEU RAPOSO DE MELLO54

Good Manufacturing Practices for Medications Technical Regulations: basic principals55

Table of Contents56

General Considerations57Glossary58Quality Management on the Manufacture of Medications: philosophy and essential elements.591 Quality Assurance602 Good Manufacturing Practices for Medications (GMP)613 Sanitation and Hygiene62

4 Qualification and Validation63 5 Complaints646 Withdrawal of Products657 Production and/or Analysis Contract668 Self Inspection and Quality Audits679 Personnel6810 Training6911 Personal Hygiene7012 Installations7113 Equipment7214 Materials73General74Raw materials75

Packaging materials76 Intermediate and bulk products77Finished products78Rejected, recovered, reprocessed and reworked materials79Withdrawn products80Returned products81Reagents and culture mediums82Reference standards83Waste materials84Various materials8515 Documentation86Principle87General88

Labels899091



92Quality control specifications and test procedures93Specifications for raw materials and packaging materials94Specifications for intermediate and bulk products95Specifications for finished products96Master / standard formulas97Packaging instructions98Batch processing records99Batch packaging records100Standard Operational Procedures – SOPs and records10116. Good production practices102General103Prevention of bacterial and cross contamination during production.104Production operations105Packaging operations10617. Good quality control practices107Control over raw materials and intermediate, bulk and finished products108Necessary tests109Raw materials and packaging materials110In-process control111

Finished products112 Batch registration review113Stability study114

ATTACHMENT I115

Sterile products 116

1 General considerations1172 Quality Control1183 Sanitation1194 Manufacture of sterile products1205 Terminally sterilized products1216 Aseptic Preparation122

7 Production123 8 Sterilization1249 Heat sterilization12510 Damp heat sterilization12611 Dry heat sterilization12712 Radiation sterilization12813 Sterilization with gases and fumigation12914 Aseptic process and sterilization through filtering13015 Personnel13116 Installations13217 Equipment13318 Finalizing of the manufacturing steps13419 Isolator technology135

20 Blowing/containerizing/sealing technology136

ATTACHMENT II137

Biological products 138

1 Reach1392 General considerations1403 Personnel1414 Installations and Equipment1425 Animal installations143

144



196General considerations 197

Registered medications must be manufactured only by authorized and licensed manufacturers, whose198activities are inspected on a regular basis by the competent national authorities. These regulations will be199used to standardize the evaluation of compliance with the Good Manufacturing Practices for Medications for 200human use during health inspections.201

GMP are applicable to all operations involved in the manufacture of medications, including medications202under development destined for clinical trials. The Good Manufacturing Practices (GMP) described in this203document are subject to continuous updating so as to follow up the evolution of new technologies.204Alternative actions may be adopted so as to comply with the specific needs of a given product, as long as205those are validated to guarantee the product’s quality.206

These regulations do not cover the aspects of occupational safety or environmental protection: these matters207are regulated by specific legislation. However, the manufacturer must guarantee the safety of its employees208and take the necessary measures to prevent polluting the environment.209

Glossary 210

The definitions furnished below are applicable to the terms used in these regulations. They may have211different meanings in other contexts.212

An techamber 213An enclosed space with two or more doors placed between two or more distinct cleanliness class areas, with214the objective of controlling the air flow between both, when they need to be entered into. The antechamber is215designed to be used by people, materials or equipment.216

Clean area 217An area with defined environmental control in terms of contamination by viable and unviable particles,218designed, built and used so as to reduce the introduction, generation and retention of contaminants in its219interior.220

Segregated area 221Installations that offer full separation of all aspects of an operation, including the movement of personnel and222equipment, with well established procedures, controls and monitoring. This includes physical barriers, as well223as separate air systems, but does not necessarily imply different and separate buildings.224

Calibration 225The set of operations that establishes, under specific conditions, the ratio between values given by an226instrument or system for measuring (for example, weight, temperature and pH), recording and controlling, or 227the values represented by a measure of material, as well as known values corresponding to a reference228standard. Acceptance limits must be established for the measurement results.229

Contamination 230The undesirable introduction of impurities of a chemical or microbiological nature, or of foreign matter in a231raw material, intermediate product and/or finished product during sampling, production, packaging or 232repackaging, storage or transportation processes.233

Cross contamination 234

The contamination of a given raw material, intermediate product, bulk product or finished product with235another raw material, intermediate product, bulk product or finished product during the production process.236

In-process control 237Verifications carried out during production so as to monitor and, if necessary, adjust the process to238guarantee that the product is according to its specifications. Control over the environment or equipment may239also be considered as a part of the in-process control.240

Retest date 241A date established by the manufacturer based on stability studies after which the material must be242reanalyzed so as to guarantee that it is still suitable for immediate use, in accordance with tests indicating243stability defined by the consumable manufacturer and as long as the pre-established storage conditions are244maintained. The retest date is only applicable when the consumable’s expiry date has not been established245by the manufacturer.246

247



248Vegetable-based drug derivative 249Products extracted from a vegetable-based drug: extract, tincture, oil, wax, exudation and others.250

Batch documentation251All documents associated with the manufacture of a bulk product or finished product batch. It furnishes the252history of each product batch, as well as of all circumstances relevant to the quality of the final product.253

Vegetable-based drug 254Medicinal plant or its parts that contain substances or classes of substances responsible for therapeutic255action after its collection, stabilization and/or drying processes, and may be whole, erased, shredded or 256pulverized.257

Packaging 258All operations, including bottleling and labeling, which the bulk product must undergo so as to become a259finished product. Normally, the sterile container is not considered a part of the packaging process, although260the bulk product is contained in the primary package.261

Specification 262A document that describes in details the requirements that the products or materials used or obtained during263manufacture must comply with. The specifications serve as a basis for the evaluation of quality.264

Manufacture 265

All operations that include the acquisition of materials, production, quality control, release, storage, issuing of 266finished products, as well as the related controls.267

Manufacturer 268Holder of the Operation Authorization for the manufacture of medications, issued by the competent authority269from the Ministry of Health, as provided for in the health legislation in force.270

Master formula / Standard formula 271Document or set of documents that specify the raw materials and packaging materials with their quantities,272together with a description of the procedures and necessary precautions for the production of a given273quantity of the finished product. Besides, it also furnishes instructions on processing, as well as on in-274process controls.275

Acti ve pharmaceut ical consumable 276

Any substance or mixture of substances that is intended for use in the manufacture of a pharmaceutical277 dosage form, which, when used in this manner, becomes an active ingredient in this pharmaceutical dosage278form. It is intended that the said substances furnish a pharmacological activity or other direct effect as to the279diagnosis, cure, mitigation, treatment or prevention of a disease or so as to affect the body’s structure and280function.281

Batch 282The defined quantity of raw material, packaging material or processed product in one or more processes,283whose essential characteristic is homogeneity. It may sometimes be necessary to split up a batch into284various sub-batches, which are thereafter grouped so as to form a final homogenous batch. In case of final285sterilization, the batch size is determined by the autoclave’s capacity. Under continuous manufacture, the286batch must correspond to a defined production fraction characterized by its intended homogeneity.287

Marker 288

A chemical compound or class of chemical compounds (e.g.: alkaloids, flavonoids, fatty acids, etc.) present289 in the vegetable-based raw material, preferably having a correlation with the therapeutic effect that is used290as a reference in the quality control of the vegetable-based raw material, as well as of phytotherapeutic291medications.292

Packaging material 293Any material, including printed material employed in the packaging of a medication, but excluding any other 294package used for its transportation or shipping. The packaging materials are classified as primary or 295secondary, in accordance with the degree of contact with the product.296

Raw material 297Any substance with a defined quality that is used in the production of a medication, but excluding packaging298materials.299

Vegetable-based raw materials300 Fresh medicinal plant, vegetable-based drug or vegetable-based drug derivative301

302



303Medication 304A pharmaceutical product technically obtained or prepared with a prophylactic, curative, palliative or 305diagnostic purpose.306

Phytotherapeutic medication 307Medication obtained by exclusively employing vegetable-based active raw materials. It is characterized308through knowledge on the efficacy and risks of its use, as well as through its reproducibility and quality309

consistency. Its efficacy and safety are validated through ethnopharmacological surveys, its usage, techno-310scientific documentation or clinical evidences. Medications that include isolated active substances in its311composition, from any source, or the associations of these with vegetable-based extracts, are considered312phytotherapeutic.313

Botanical nomenclature 314Species (E.g.: Calendula officinalis).315

Full official botanical nomenclature 316Genus, species, variety, binomial author and family.317

Batch number 318A defined combination of numbers and/or letters that identifies, in a unique manner, a batch in its labels,319batch documentation, and corresponding analysis certificates, among others.320

Critical operation 321Operation during the manufacturing process that may cause a variation in the quality of the medication.322

Production Order 323A document or set of documents that serve as a basis for the batch documentation to be filled in with the324data obtained during production and that contemplates the master formula’s / standard formula’s information.325

Large scale parenterals 326Sterile solutions destined to parenteral application with a volume of 100 mL or more packaged in the same327container.328

Worst Case 329A condition or set of conditions that present the greatest possibilities of defect in the product or process330when compared to ideal conditions. Such conditions do not necessarily include deviations in the product or 331

process.332Master Validation Plan (MVP) 333The Master Validation Plan is a document of a general level that establishes a validation plan for the project334as a whole, summarizes the manufacturer's general philosophy and approach with the aim of establishing a335suitable performance. It provides information on the manufacturer’s validation work program, defines details336and a schedule for the work to be undertaken, including the definition of responsibilities for the337implementation of the plan.338

Standard Operational Procedure (SOP) 339An authorized procedure in writing supplying instructions to carry out operations that are not necessarily340specific to a given product or material, but of a general nature (for example, operation, maintenance and341cleaning of the equipment; validation; cleaning of installations and environmental control; sampling and342inspection). Certain procedures may be used to supplement the batch production master documentation of a343

specific product.344Production 345All operations involved in the preparation of a given medication from the receiving of the materials from346stores, going through processing and packaging until the finished product is obtained.347

Bulk product 348Any product that has passed through all of the production steps, without including the packaging process.349Injectables in their primary package are considered a bulk product.350

Intermediate product 351A partially processed product that must undergo further manufacturing steps before becoming a bulk352product.353

354



355Finished product 356A product that has passed through all production processes, including labeling and final packaging.357

Validation Protocol (or Plan) (VP) 358A document that describes the activities to be carried out during validation, including acceptance criteria for 359the approval of a production process or part of it for routine usage.360

Qualification 361A set of actions carried out to attest and document that any installations, systems and equipment are362properly installed and/or operating correctly and lead to the expected results. Qualification is frequently a363part of the validation (the initial stage), but the individual qualification steps do not on their own constitute a364process validation.365

Project Qualification (PQ) 366Documented evidence that the installations, support systems, utilities, equipment and processes were367designed according to the GMP requirements.368

Performance Qualification (PQ) 369Documented verification that the equipment or system is operating in a consistent and reproducible manner,370in accordance to defined parameters and specifications, for extended periods (within the system context, the371term “process validation” may also be used).372

Installation Qualification (IQ) 373A set of operations carried out to ensure that the installations (such as equipment, measuring instruments,374utilities and manufacturing areas) used in the production processes are appropriately selected and correctly375installed and operate in accordance with the established specifications.376

Operation Qualification (OQ) 377A set of operations that establishes, under specific conditions, that the system or subsystem presents a378performance as foreseen in all of its considered operational ranges. All equipment used in executing the379tests must be marked and calibrated before being used.380

Quarantine 381Condition of raw materials, packaging materials, intermediate or bulk products or finished products that are382physically isolated or through other efficient means whilst awaiting for a decision on their release, rejection or 383reprocessing.384

Reanalysis 385Analysis carried out on raw materials that have been previously analyzed and approved so as to confirm the386maintenance of the specifications established by the manufacturer, within its validity term.387

Reconciliation 388A procedure that has as its objective to make a comparison between the different manufacturing steps of a389product batch, between the real production quantity and the theoretically established production quantity.390

Recovery 391Full or partial incorporation of prior batches of proven quality to another batch at a defined step in production.392

Validation Report (VR) 393A document in which the records, results and evaluation of a validation program are consolidated and394summarized. It may also contain proposals for improvement of the processes and/or equipment.395

Shipping or delivery396A quantity of a given material made by a manufacturer and supplied in response to a purchase order.397Shipping may include one or more volumes and may include materials belonging to more than one batch.398

Reprocessing 399Reworking of the entire batch or part thereof of a product outside of one or more established quality400parameters, from a defined production step, so that its quality may become acceptable through one or more401additional operations. Reprocessing must be authorized beforehand and carried out in accordance with402approved procedures. Reprocessing is an unexpected occurrence.403

Respons ible Technician 404The individual acknowledged by the national regulatory authority as the one being responsible for 405guaranteeing that each finished product batch has been manufactured, tested and approved for release in406

accordance with the laws and regulations in force in the country.407408



4531. Quality assurance 454

1.1 Principle. “Quality assurance” is a very broad concept that covers all subjects that either 455individually or collectively influence the quality of a product. This deals with all of the measures taken with456the objective of guaranteeing that the medication is within the required quality standards, so that it may be457used for its proposed purposes. Therefore, Quality Assurance incorporates the GMP as well as other factors,458including the design and development of a product, which are not contemplated in the purposes of these459regulations.460

1.2. The quality assurance system appropriate for the manufacture of medications must guarantee461that:462

(a) the medication is planned and developed in such a manner that it considers the GMP463requirements, as well as other ones, such as those of the good laboratory practices (GLP) and464good clinical practices (GCP);465

(b) the production and control operations are clearly specified in writing and that the GMP466requirements are complied with;467

(c) the management responsibilities are clearly specified in the post’s description;468

(d) measures are taken for the correct manufacture, distribution and use of raw materials and469packaging materials;470

(e) all necessary controls are exercised over the raw materials, intermediate products and bulk471products, as well as other in-process controls, calibrations and validations;472

(f) the finished product is correctly processed and checked, in consonance with the defined473procedures;474

(g) the medication is not sold or supplied before the authorized individuals have certified that each475production batch has been produced and controlled in accordance with the registration476requirements and any other regulations relevant to the production, control and release of 477medications;478

(h) instructions are supplied and the necessary measures are taken to guarantee that the479medication is stored by the manufacturer, distributed and subsequently handled so that its480quality is maintained throughout its validity term;481

(i) there is a self inspection procedure and/or an in-house quality audit that regularly evaluates the482efficacy and applicability of the quality assurance system;483

(j) any deviations are reported, investigated and recorded;484

(k) there is a change control system that may have an impact on the product’s quality;485

(l) regular evaluations of the medication’s quality must be carried out with the objective of verifying486the consistency of the process and ensuring its continuous improvement.487

1.3 The manufacturer is responsible for the quality of the medications manufactured by it, ensuring488

that these are suitable for the purposes to which they are destined, that they comply with the requirements489 established in their records and do not put the patients at risk by presenting inadequate safety, quality or 490efficacy. Compliance with this objective is the company’s top management’s responsibility and requires the491participation and commitment of the employees in the various departments throughout all levels of the492organization, of the supplying companies and the distributors. So that the quality objective is attained in a493reliable manner, there must be a fully structured Quality Assurance system that is correctly implemented and494that incorporates the GMP. This system must be fully documented and have its effectiveness monitored. All495parts of the Quality Assurance system must be made up of trained and competent personnel, besides having496sufficient and suitable space, equipment and installations.497

498



4992. Good Manufacturing Practices fo r medications (GMP) 500

2.1 Good Manufacturing Practices is the part of Quality Assurance that ensures that the products are501consistently produced and controlled, with quality standards that are appropriate for their intended and502registration-required use. Compliance with the GMP is directed firstly to diminishing the risks that are503inherent to any pharmaceutical production, which may not be detected by carrying out tests on finished504products. The risks are essentially constituted by: cross contamination, contamination with particles and505changing or mixing of products. The GMP determine that:506

(a) all manufacturing processes must be clearly defined and systematically reviewed based on the507acquired experience. Besides this, they must also show themselves able to manufacture508medications within the required quality standards, complying with the respective specifications;509

(b) the necessary qualifications and validations are carried out;510

(c) all of the necessary resources are supplied, including:511

(i) duly trained and qualified personnel;512

(ii) suitable installations and space;513

(iii) suitable equipment and services;514

(iv) appropriate materials, containers and labels;515

(v) approved procedures and instructions;516

(vi) suitable transportation and storage;517

(vii) installations, equipment and qualified personnel for in-process control;518

(d) the instructions and procedures must be written in a clear, unequivocal language and519specifically applicable to the installations used;520

(e) the operators must be trained to correctly perform the procedures;521

(f) records must be made (manually and/or through recording instruments) during the522manufacture to show that all steps listed in the procedures and instructions were complied523

with, and that the quantity and quality of the obtained product are in conformity with the524 expected. Any significant deviation must be recorded and investigated;525

(g) the records referring to the manufacture and distribution, that enable the full tracking of a526batch, are filed in an organized manner and easily accessible;527

(h) the appropriate storage and the distribution of the products must minimize all risks to their 528quality;529

(i) a system that is able to withdraw any batch after it has been sold or supplied is implemented;530

(j) complaints on products that have been sold must be examined and recorded, as well as the531causes for the quality deviation must be investigated and documented. Measures must be taken in relation to532the products with quality deviation and actions must be adopted in the sense of preventing recurrences.533

3. Sanitation and hygiene534

3.1 The manufacturing of medications requires a high level of sanitation and hygiene that must be535observed in all of its procedures. Sanitation and hygiene activities must cover personnel, installations,536equipment and devices, production materials and containers, cleaning and disinfection products and any537other aspect that may constitute a source of contamination of the product. Potential sources of contamination538must be eliminated by means of a broad sanitation and hygiene program.539

540



5414. Qualification and validation 542

4.1 In consonance with the GMP, the company must identify which qualification and validation543works are necessary to prove that all critical aspects of operation are controlled.544

4.2 The key elements for a qualification and validation program within a company must be clearly545defined and documented in a master validation plan.546

4.3 Qualification and validation must establish and prove that:547(a) the installations, utilities, equipment, and processes were designed in consonance with548

the GMP requirements (project qualification, or PQ);549

(b) the installations, utilities, and equipment were built and installed in accordance with their 550project specifications (installation qualification, or IQ);551

(c) the installations, utilities, and equipment operate in accordance with their planned552specifications (operation qualification, or OQ);553

(d) a specific process will consistently produce a product that complies with its554specifications and quality attributes (process validation or PV, also called performance555qualification, or PQ).556

4.4 Any of the operation’s aspects, including significant changes to the installations, location,557 equipment or processes, that may affect the quality of the product, either directly or indirectly,558must be qualified and/or validated.559

4.5 Qualification and validation must not be considered one-off exercises. After the approval of the560qualification and/or validation report, there must be a continuous monitoring program, which561must be based on a periodic review.562

4.6 The commitment to the maintenance of the qualification/validation situation must be described563in the company’s relevant documents, as the quality manual or master validation plan.564

4.7 The responsibility for carrying out the validation must be clearly defined.565

4.8 Validation studies are an essential part of the GMP and must be carried out in accordance with566predefined and approved protocols.567

4.9 A report containing the results and conclusions must be prepared and filed.568

4.10 The processes and procedures must be established based on the results of the validation569carried out.570

4.11 The cleaning procedures must also be validated, as well as the analytical methodologies and571the computerized systems.572

5. Complaints573

5.1 Principle. All complaints, as well as all other information with reference to products with574possible quality deviation, must be carefully investigated and recorded in accordance with575written procedures. Corrective actions must be taken.576

5.2 An individual responsible for receiving the complaints, as well as for the measures to be taken577must be designated. This individual must have sufficient supporting personnel to assist him/her 578in his/her function. If this individual is not the Responsible Technician, the latter one must be579aware of any complaint, investigation or withdrawal.580

5.3 In case of complaints of possible quality deviations of a product, procedures in writing must be581adopted that describe the actions to be adopted, including the need to carry out a probable582withdrawing.583

5.4 The company must identify if a complaint is as a result of falsification and adopt the pertinent584measures.585

586



5875.5 Any complaint with reference to quality deviations in a given product must be recorded together 588

with all the batch registration details and, subsequently, it must be fully investigated. The589individual responsible for the Quality Control must be involved in the study of the deviation in590question.591

5.6 If any quality deviation is detected in a product batch or if there is a possibility of deviation in a592given batch, it must also be taken into consideration the possibility that other batches present593

the same problem and, therefore, these ones must be checked. Other batches that contain the594reprocessed product of the batch with deviation must be especially investigated.595

5.7 When necessary, suitable follow-up measures must be taken after the investigation and596evaluation of the complaint, including the possibility of withdrawing the product.597

5.8 All decisions and measures taken as a result of a certain complaint must be recorded and598mentioned in the records of the corresponding batch.599

5.9 Complaint records must be reviewed on a regular basis with the purpose of detecting600evidences of any specific or recurrent problem that requires greater attention and may justify601the withdrawing of the products sold.602

5.10 The competent health authorities must be informed by the manufacturer when any significant603quality deviation in the manufacturing process, or deterioration of the product is detected or 604

when some other serious problem regarding the quality of any product is being investigated.605

6. Withdrawal of Products606

6.1 There must be a system that immediately and effectively withdraws from the market any607product that presents a quality deviation or is under suspicion.608

6.2 A responsible individual must be designated for the measures to be adopted, as well as for the609coordination of the withdrawal of the product from the market. This individual must have610sufficient supporting personnel to assist him/her in all aspects of the withdrawal with the611necessary degree of urgency. Normally, this individual must not belong to the sales and612commercialization body and, in case he/she is not the Responsible Technician, then this one613must be informed of any action that is taken.614

6.3 There must be written procedures that are regularly checked and updated to proceed with any615withdrawal activity. The operations of product withdrawal from the market must be immediate,616preferentially starting with hospitals and pharmacies. Procedures that contemplate the617destination of the withdrawn products that have been deviated from the transportation and/or 618distribution chain must be foreseen.619

6.4 There must be written procedures that describe the storage of the withdrawn products in a620secure and separate area whilst their final destination is being decided upon.621

6.5 All competent health authorities of the countries to which the product has been shipped must622be immediately informed on any intention of withdrawing the product that presents or is under 623suspicion of a quality deviation.624

6.6 The records of distribution of batches must be readily available and must contain sufficient625information on distributors and direct clients, including the products that have been exported,626samples for clinical testing, and medical samples, in such a manner that they may be efficiently627withdrawn.628

6.7 The progress on the withdrawing process must be monitored and recorded. The records must629include the disposition of the product. A final report must be issued, including the reconciliation630between the quantities distributed and those withdrawn of the products.631

6.8 The efficacy of the withdrawal measures must be periodically tested and evaluated.632

633



6347. Produc tion and/or Analysis Contract 635

7.1 Principle. Production and/or analysis contracts must be clearly defined, agreed upon and636controlled in such a manner to avoid erroneous interpretations that may result in a product,637process or analysis of unsatisfactory quality.638

General6397.2 All conditions established in the production and/or analysis contract, including any proposals of 640

change to technical conditions or any other change, must be in accordance with the product641registration.642

7.3 The contract must allow the contracting party to audit the contracted party’s installations.643

7.4 In case of an analysis contract, the final approval for releasing the product for it to be644commercialized must be carried out by the Responsible Technician of the contracting645company.646

The contracting party647

7.5 The contracting party is responsible for evaluating the competence of the contracted party in648 correctly carrying out the contracted processes or tests, for the approval of the contract649activities, as well as for the assurance, in the contract, that the GMP principles described in650these regulations are complied with.651

7.6 The contracting party must furnish the contracted party with all of the information necessary to652carry out the contracted operations in a correct manner, according to the product registration653and any other legal requirements. The contracting party must ensure that the contracted party654is informed of any problems associated with the product, process or tests that may place the655installations, equipment, personnel, materials or any other products at risk.656

7.7 The contracting party must ensure that all processed products and materials delivered by the657contracted party comply with their specifications or that the product has been released by the658Responsible Technician.659

The contracted party660

7.8 The contracted party must have suitable installations, equipment and knowledge, besides661experience and qualified personnel to satisfactorily carry out the services requested by the662contracting party. The manufacturing contract may only be carried out by manufacturers that663have Operating Licenses, as well as Sanitation Certificates.664

7.9 It is forbidden for the contracted party to outsource any part of the work entrusted to it in the665contract.666

7.10 The contracted party must abstain from any activity that may negatively affect the quality of the667manufactured and/or analyzed product for the contracting party.668

The contract669

7.11 There must be a contract in writing between the contracting party and the contracted party that670clearly establishes the responsibilities of each party.671

7.12 The contract must clearly affirm the manner in which the Responsible Technician must672exercise his/her full responsibility, as well as ensure that each batch has been manufactured673and checked, in accordance with the registration requirements, when liberating each batch of 674the product for sale or issuing an analysis certificate,.675

7.13 The technical aspects of the contract must be established by competent individuals with676suitable knowledge in technology, analysis and GMP in the pharmaceutical area.677

7.14 All measures for production and analysis must be in accordance with the registration and must678be agreed upon by both parties.679

680



6817.15 The contract must clearly describe the responsibilities for the acquisition, control testing and682

release of materials, for the production and for carrying out the quality controls, including the683in-process controls, as well as the responsibility for sampling and carrying out analyses. In684case of an analysis contract, the contract must state if the contracted party must either or not685collect samples at the manufacturer’s installations.686

7.16 The production, analysis, and distribution records, as well as the reference samples must be687

kept by the contracting party or be available to it. Any relevant records to evaluate the quality of 688a product in case of complaints or suspicion of deviations must be accessible and specified in689the contracting party’s procedures on deviations/withdrawal.690

7.17 The contract must describe the management of raw materials, intermediate, bulk and finished691products in case they are rejected. It must also describe the procedure to be followed in case692the contracted analysis shows that the tested product must be rejected.693

8. Self inspection and qualit y audits6948.1 Principle. The objective of self inspection is to evaluate the compliance, by the manufacturer,695

with the GMP in all aspects of production and quality control. The self inspection program must696be planned to detect any eventualities in implementing the GMP, as well as to recommend the697necessary corrective actions. Self inspections must be carried out in a routine manner and698

may, besides this, be carried out in special occasions, for example, in case of withdrawals or 699repeated rejection of products, or when an inspection is announced by health authorities. The700team responsible for the self inspection must consist of personnel that are able to objectively701evaluate the implementation of the GMP. All recommendations for corrective actions must be702implemented. The self inspection procedure must be documented and there must be an703efficient follow-up program.704

Items for self inspection705

8.2 Procedures in writing must be established for self inspection with the purpose of furnishing a706minimum and uniform standard of requirements. These procedures may include questionnaires707on GMP requirements, covering at least the following aspects:708

(a) personnel;709 (b) installations, including dressing rooms;710(c) maintenance of buildings and equipment;711(d) storage of raw materials, intermediate products and finished products;712(e) equipment;713(f) production and in-process controls;714(g) quality control;715(h) documentation;716(i) sanitation and hygiene;717(j) validation and revalidation programs;718(k) calibration of instruments or measuring systems;719(l) withdrawal procedures;720(m) complaints management;721

(n) control over labels;722 (o) results of prior self inspections, as well as any corrective measures taken.723

Self inspection team724

8.3 Quality Assurance must name a team to conduct self inspection, made up of qualified725professionals who are specialized in their individual areas of operation and familiar with the726GMP. The team’s members may be professionals from the company itself or external727specialists.728

Self inspection frequency729

8.4 The frequency with which self inspections are carried out may depend on the company’s730requirements, and they must preferentially be carried out at least once a year. The frequency731

must be established in a procedure.732733



734Self inspection report735

8.5 A report must be drawn up after the end of a self inspection. The report must include:736

(a) the self inspection results;737(b) the evaluation and conclusions;738(c) the recommended corrective actions.739

Follow up action7408.6 There must be an efficient follow-up program. The company’s administration must evaluate741

both the self inspection report and the recommended corrective actions, if necessary.742

Quality audit743

8.7 A complement to the self inspections with quality audits may be necessary. The quality audit744consists of a test and an evaluation of the entire part or of a part thereof of a given quality745system, with the specific objective of improving it. In general, this is carried out by external,746independent specialists, or by a team designated by management for the said purpose.747Besides this, the audits may be extended to suppliers and contracted parties.748

Audi ts and supp lier approval749

8.8 The individual designated to control the quality must have joint responsibility with the other 750 relevant departments to approve reliable suppliers of raw materials and packaging materials751that comply with the established qualifications.752

8.9 Before suppliers are approved and added to the list or specifications of approved suppliers,753they must be evaluated. The evaluation must consider the supplier’s history, as well as the754nature of the materials to be supplied. If an audit is necessary, then this must prove the755supplier’s capacity in complying with the GMP standards.756

9. Personnel757

9.1 Principle. The establishment and maintenance of a Quality Assurance system and the758manufacture of medications depend on the individuals carrying them out. It is for this reason759that there must be qualified personnel in sufficient quantity to perform all of these activities for 760which the manufacturer is responsible. All of the individual responsibilities must be established761in written procedures and be clearly understood by all those involved.762

General763

9.2 The manufacturer must have a suitable number of individuals with the necessary qualifications764and practical experience. The responsibilities attributed to any employee must not be so765extensive to a point of presenting risks to the quality of the product.766

9.3 The company must have a flowchart. All employees who have positions of responsibility must767have their specific functions described in writing and sufficient authority to carry them out. Their 768functions may be delegated to designated substitutes that have the satisfactory qualification769level. There may be no lack or overlapping of responsibilities by the personnel with reference to770the applying of the GMP.771

9.4 All personnel must know the GMP principles and receive initial and continuous training,772 including instructions on hygiene, according to the need. All personnel must be motivated to773support the company in maintaining the quality standards.774

9.5 Measures must be taken to prevent unauthorized individuals from entering the production,775storage and quality control areas. Personnel not working in these areas must not use them as776a thoroughfare to other areas.777

Key personnel778

9.6 Key personnel include the persons responsible for production, quality assurance, quality779control, and the Responsible Technician. Normally, key posts must be taken up by individuals780that are employed full time. Those responsible for production and quality control must be781independent from one another. In large scale companies, it may be necessary to delegate782some functions; nevertheless, responsibility may not be delegated.783

784



7859.7 Key personnel responsible for production, quality assurance, and quality control over 786

medications must have practical experience and the qualification required by legislation. Their 787education level must include a combination of studies in the following fields of knowledge:788

(a) chemistry (analytical or organic) or biochemistry;789(b) chemical engineering;790(c) microbiology;791

(d) pharmaceutical sciences and technology;792(e) pharmacology and toxicology;793(f) physiology;794(g) other related sciences.795

9.8 Those responsible for Production, Quality Control and Assurance must jointly carry out certain796activities related to quality, such as:797

(a) authorization of procedures and documents, including their updates;798(b) monitoring and control of the manufacturing environment;799(c) establishment and monitoring of hygiene conditions;800(d) process validation and calibration of analytical instruments;801(e) training, including the applying of quality assurance principles;802

(f) approval and monitoring of materials suppliers;803(g) approval and monitoring of contracted manufacturers;804(h) specifications and monitoring of the conditions of storage of materials and products;805(i) in-process controls;806(j) filing of documents/records;807(k) monitoring of the compliance with the GMP;808(l) inspection, investigation and sampling, so as to monitor factors that may affect the809

product’s quality.810

9.9 The individual responsible for production generally has the following responsibilities:811

(a) ensure that the products are manufactured and stored in accordance with appropriate812procedures, with the objective of achieving the required quality;813

(b) approve the instructions related to production operations, including in-process controls,814

and ensure the strict implementation of these;815(c) ensure that the production records are evaluated and signed by an indicated individual;816(d) verify the maintenance of the installations and equipment;817(e) ensure that the validations of the processes, calibrations and control over the equipment818

are carried out and recorded, as well as make sure that the reports are available;819(f) ensure that initial and continuous training is given to the production area personnel and820

that such training is suitable to the needs.821

9.10 The individual responsible for Quality Control has the following responsibilities:822

(a) approve or reject raw materials, packaging materials and intermediate, bulk and finished823products;824

(b) evaluate the batch records;825

(c) ensure that all of the necessary tests are carried out;826

(d) approve the instructions for sampling, the specifications, test methods and quality827control procedures;828

(e) approve and monitor the analyses carried out under the contract;829

(f) verify the maintenance of the installations and equipment;830

(g) ensure that the necessary validations are carried out, including the validation of 831analytical procedures and the calibration of control equipment;832

(h) ensure that initial and continuous training is given to the Quality Control area personnel,833in accordance with the sector’s needs.834

835



8369.11 The Responsible Technician must ensure the compliance with the technical and regulatory837

requirements related to the quality of finished products and their approval for sale.838

9.12 The Responsible Technician is also involved in other activities, including the following:839

(a) implementation and, when necessary, establishment of the quality system;840(b) participation in developing the company’s quality manual;841(c) supervision of self inspections;842(d) general knowledge of the quality control department;843(e) participation in external audits (audits on suppliers);844(f) participation in validation programs.845

9.13 The function of approving the release of a batch or finished product may be delegated to an846individual with the appropriate qualification and experience, who will release the product in847accordance with the approved procedures, which is normally carried out by quality assurance848by means of reviewing the batch’s documentation.849

9.14 The individual responsible for the approval and release of a batch must always ensure that the850following requirements are complied with:851

(a) the product’s registration requirements were complied with for the batch in question;852(b) the Good Manufacturing Practices principles and directives were complied with;853

(c) the manufacturing and control processes were validated;854(d) that all of the necessary verifications and tests were carried out, considering the855

manufacturing registration and conditions;856(e) any planned changes, deviations in manufacture or quality control were notified in857

accordance with a well defined system before releasing any product. The said changes858may need notification and approval from the regulating authority.859

(f) any additional changes in sampling, inspection, tests and verifications have been carried860out or started, to comply with the planned changes or deviations found;861

(g) all of the necessary production and quality control documentation has been completed862and approved by the respective supervisors;863

(h) appropriate and accurate audits, self inspections and verifications were carried out by864experienced and trained teams;865

(i) that the quality control attests the full compliance with the specifications;866

(j) that all relevant factors were considered, including any others that were not specifically867associated with the production batch under review.868

10. Training869

10.1 The manufacturer must, through a written and defined program, train the individuals involved in870the production areas, in the quality control laboratories, as well as all personnel whose871activities may have an effect on the quality of the product.872

10.2 Besides the basic training on the theory and practice of GMP, recently hired personnel must873also receive specific training on their work post. Continuous training must also be given and its874practical effectiveness must be periodically evaluated. Approved training programs must be875available and records on the training must be kept.876

10.3 Personnel working in clean areas, in areas where there is a risk of contamination, where highly877active, toxic, infectious or sensitizing materials are handled must receive specific training.878

10.4 The concept of quality assurance and all the measures that assist in its understanding and879implementation must be fully discussed during the training sessions.880

10.5 Visitors or untrained personnel must not enter, preferentially, into the production and quality881control areas. In case this is inevitable, then they must be furnished with the relevant882information beforehand, in particular about personal hygiene, as well as the appropriate883protection clothing, and must be accompanied by a designated professional.884

10.6 Consulting and contracted parties’ teams must be qualified for the training services that they885render. Evidences of their qualification must be included in the training records.886

887



88811. Personal hygiene889

11.1 All personnel, before and during their time of service, as appropriate, must be subjected to890health checks. Employees that carry out visual inspections must also be subjected to periodic891ophthalmologic tests.892

11.2 All personnel must be trained in personal hygiene practices. All individuals involved in the893

manufacturing processes must comply with the hygiene regulations; in particular, they must be894instructed to wash their hands before entering the manufacturing areas. For this to complied895with, instructive signs must be put up and observed.896

11.3 Individuals that are suspected of or with confirmed diseases or open wounds that may897adversely affect the quality of the products may not handle raw materials, packaging materials,898intermediate and bulk products or finished products until their health condition does not present899a risk to the product.900

11.4 All employees must be instructed and encouraged to report to their immediate supervisor any901conditions related to production, equipment or personnel that they consider may adversely902interfere with the products.903

11.5 Direct contact between the operator’s hands and raw materials, primary packaging materials904

and intermediate or bulk products must be avoided.90511.6 To assure that the product is protected against contamination, the employees must use clean906

clothing appropriate to each production area. The uniforms, in case they are reusable, must be907stored in a closed environment until they are washed, and when necessary disinfected or 908sterilized.909

11.7 The uniforms must be furnished by the manufacturer in accordance with written procedures.910The washing of the uniforms is the company’s responsibility.911

11.8 For the employee’s protection to be assured, the manufacturer must make available Collective912Protection Equipment (CPE), as well as Individual Protection Equipment (IPE), in accordance913with the activities carried out.914

11.9 It is forbidden to smoke, eat, drink, chew gum or keep plants, food stuff, drinks, tobacco and915

personal medication within the production areas, quality control and storage laboratory or in916 any other areas in which the said actions may adversely affect the product’s quality.917

11.10 Personal hygiene procedures, including the use of appropriate clothing, are applicable to all918individuals that enter the production areas.919

12. Installations920

12.1 Principle. The installations must be located, planned, built, adapted and maintained so that921they are suitable for the operations to be carried out.922

General 923

12.2 Their project must minimize the risk of errors, as well as enable cleaning and maintenance, so924 as to prevent cross contamination, the accumulation of dust and dirt or any adverse effect that925may affect the quality of the products.926

12.3 Measures must be taken to prevent cross contamination and to facilitate cleaning when there is927a dispersion of powders, as during sampling, weighing, mixing, processing and packaging of 928powders operations.929

12.4 The installations must be located in an environment that, when considered together with the930measures to protect the manufacturing process, will present a minimum risk of causing any931contamination of materials or products.932

12.5 Installations used in the manufacture of medications must be designed and built so as to933enable adequate cleaning.934

12.6 The installations must be kept in a good state of preservation, hygiene and cleanliness. It must935 be ensured that the maintenance and repair operations do not present any risk to the quality of 936the products.937

938



939

12.7 The installations must be cleaned, and when applicable disinfected, in accordance with940detailed written procedures. Records on the cleaning must be kept.941

12.8 The supply of electrical power, illumination, air conditioning (temperature and humidity), as well942as ventilation must be appropriate, so as to not directly or indirectly affect the medications943during the manufacturing and storage processes or the adequate operation of the equipment.944

12.9 The installations must be planned and equipped so as to offer maximum protection against the945entry of insects, birds or other animals. There must be a procedure to control rodents and946pests.947

12.10 The installations must be planned so as to guarantee the logical flow of materials and948people.949

Auxi liary areas950

12.11 The rest rooms and refectories must be separated from the manufacturing and control951areas.952

12.12 The dressing rooms and bathroom installations must be easily accessible and appropriate953for the number of users. The bathrooms must not have any direct connection with the954

production or storage areas.955

12.13 The maintenance areas must be located in separate locations from the production areas. If 956the replacement parts and tools are kept in the production areas, they must be in rooms or 957cupboards that are reserved for this purpose.958

12.14 The animal room must be isolated from the other areas and have a separate entry and an959exclusive ventilation system.960

Storage Areas961

12.15 The storage areas must have sufficient capacity to enable the ordered storage of different962categories of materials and products: raw materials; packaging materials; intermediate963products; bulk and finished products, under a quarantine condition, approved, rejected,964

returned or withdrawn, with the appropriate segregation and separation, or have a system that965 allows for the organization of the different categories and conditions.966

12.16 The storage areas must be designed or adapted to ensure ideal storage conditions. They967must be clean, dry, sufficiently organized and maintained within the acceptable temperature968limits. In cases where special storage conditions are necessary (for example, temperature,969humidity), these must be provided, controlled, monitored and recorded when appropriate.970

12.17 The receiving and shipping areas must be separated and must protect the materials and971products from climatic excursions. If it is impossible to keep them separate, appropriate972procedures must be adopted to prevent their mixture. The receiving areas must be973designed and equipped to allow for the containers to be cleaned, if necessary, before being974stored.975

12.18 Products under quarantine must be in a restricted and separate area within the storage976 area. This area must be clearly demarcated and the access to it may only be carried out by977authorized individuals. Any other system that substitutes physical quarantine must offer 978equivalent security levels.979

12.19 The storage of returned, rejected or withdrawn products and materials must be carried out980in a separate area.981

12.20 Highly active and radioactive materials, narcotics or other dangerous medications, and982substances that present special risks of abuse, fire or explosion must be stored in secure,983protected, identified and, when appropriate, separate areas, in accordance with the specific984legislation in force.985

12.21 Printed packaging materials are considered critical to the quality of medications as for their 986labeling, and special attention must be given to the safe sampling and storage of these987

materials.988

12.22 Normally, there must be a separate area for the sampling of raw materials. In case the989sampling is carried out within the storage area, it must be done in such a manner so as to990



prevent contamination or cross contamination.991

992



993Weighing area994

12.23 The weighing of raw materials must be carried out in a separate and protected area995specifically designed for this purpose, for example, with measures for powders control. The996said area may be part of the stores or production area.997

Production areas998

12.24 So as to minimize the risk of serious health problems due to cross contamination, dedicated999and separate installations must be used for the production of certain medications, such as1000biological preparations (e.g. live microorganisms) and highly sensitizing materials (e.g.1001penicillin, cephalosporin, and carbapenemic, as well as other beta-lactamic derivatives). For 1002highly sensitizing materials, separation must also occur between them. The production of 1003certain highly active products, such as some antibiotics, certain hormones and cytotoxic1004substances must be carried out in separate areas. In exceptional cases, such as accidents1005(fire, flooding, etc) or emergency situations (war, etc), the work principle under campaign in1006the same installations may be accepted, as long as specific precautions are taken and the1007necessary validations are carried out (including cleaning validation).1008

12.25 The physical installations must be arranged according to continuous operational flow, so as1009to allow production to correspond to the sequence of production operations and to the1010

required cleaning levels.101112.26 The production and storage areas must allow for the logical and ordered positioning of 1012

equipment and materials so as to minimize the risk of mixture between the different1013medications or their components and to prevent the occurrence of cross contamination, as1014well as to diminish the risk of omission or erroneous application of any manufacturing or 1015control step.1016

12.27 In the areas in which the raw materials, primary packaging materials, intermediate or bulk1017products are exposed to the environment, the interior surfaces ( walls, floor and ceiling)1018must be lined with a smooth, impermeable, washable, and resistant material, free from1019 joints, cracks and easy to clean, allowing for it to be disinfected, and must not release any1020particles.1021

12.28 The piping, light fittings, ventilation points and other installations must be designed and1022 installed so as to facilitate cleaning. Whenever possible, the access for maintenance must1023be located outside the production areas.1024

12.29 The drains must be of a suitable size, with siphons, so as to prevent the reflux of fluids or 1025gases, and they must be kept closed. Whenever possible, the installation of open channels1026must be avoided. If necessary, they must be shallow to facilitate cleaning and disinfection.1027

12.30 The production areas must be effectively ventilated, with air control installations suitable for 1028the products that are handled, for the operations that are carried out, as well as for the outer 1029environment. The production areas must have an effective ventilation system, with air 1030control units (including the filtering of air to a sufficient level so as to prevent contamination1031and cross contamination, as well as temperature and, when necessary, humidity control)1032that are appropriate for the products handled in such areas. These areas must be regularly1033

monitored during production and rest periods, with the purpose of ensuring the compliance1034 with the area’s specifications.1035

12.31 The installations for packaging of medications must be specifically planned and built so as1036to prevent mixing or cross contamination.1037

12.32 The production areas must be well illuminated, particularly where visual controls are carried1038out.1039

Quality contro l areas1040

12.33 The quality control laboratories must be separate from the production areas. Areas that1041employ biological, microbiological or radioisotope test methods must be separated from one1042another.1043

12.34 The quality control laboratories must be planned so that they are adapted to the operations1044 to be carried out in them. There must be sufficient space to prevent mixing and cross1045contamination. There must be suitable storage space for the samples, reference standards1046(if necessary with refrigeration), solvents, reagents and records.1047

1048



109814.4 All input materials and finished products must be placed under quarantine immediately after 1099

being received or produced, until they are released for use or distribution.1100

14.5 All materials and products must be stored under the appropriate conditions established by1101the manufacturer and in an orderly manner so as to allow for the segregation of batches1102and stock rotation, complying with the rule ‘first to expire, first out’.1103

14.6 The water used in the manufacture of pharmaceutical products must be suitable for its1104intended use.1105

Raw materials1106

14.7 The acquisition of raw materials is an important operation that must be carried out by a1107trained and qualified team.1108

14.8 The raw materials must only be acquired from qualified suppliers that are included in the1109company’s suppliers list, preferentially directly from the producer. The specifications1110established by the manufacturer regarding the raw materials must be discussed with the1111suppliers. All aspects of production and control over raw materials, the acquisition process,1112handling, labeling, and the requirements with reference to packaging, as well as all1113complaint procedures and rejections, must be discussed between the manufacturer and the1114

suppliers.111514.9 For each delivery, the containers must be checked at least as to the packaging and seal1116

integrity, and as to the correspondence between the order, delivery invoice and labels from1117the suppliers.1118

14.10 All materials received must be checked so as to ensure that the delivery is in accordance1119with the order. The containers must be clean and, when necessary, labeled with the1120necessary information. When additional labels are attached to the containers, the original1121information must not be obliterated.1122

14.11 Damages to the containers or any other problems that may affect the quality of the raw1123materials must be recorded and reported to the quality control department, and must be1124investigated.1125

14.12 If a delivery of materials contains different batches, then each batch must be considered1126 separately for sampling, analysis and release.1127

14.13 The raw materials placed in the storage area must be suitably labeled. The labels must1128have at least the following information:1129

(a) name of the raw material and the respective in-house reference code, when1130applicable;1131

(b) batch number attributed to it by the producer/supplier, as well as the number given to1132it by the company upon receiving;1133

(c) condition of the raw material during storage (under quarantine, under analysis,1134approved, rejected, returned, withdrawn);1135

(d) manufacturing date, retesting date or validity term and, when applicable, reanalysis1136date.1137

Identification by means of a validated electronic system is permitted. In that case, it will not be1138necessary that all of the above given information is furnished on the label.1139

14.14 There must be adequate procedures or measures to ensure the identity of the contents of 1140each raw material container. Containers from which samples have been drawn must be1141identified. (Please also see item 17.15)1142

14.15 Only raw materials that have been released by the quality control department must be1143used.1144

14.16 The raw materials must be split up by designated employees only, and in accordance with1145written procedures. The raw materials must be carefully weighed or measured in clean and1146correctly identified containers.1147

14.17 Raw materials that have been split up, as well as their respective weights or volumes, must1148be checked by another employee and the check must be recorded.1149

1150



115114.18 Split up raw materials for each production batch must be kept together and visibly identified1152

as such.1153

Packaging Material1154

14.19 The acquisition, handling and quality control of the primary and secondary packaging1155

materials, and printed materials must be carried out in the same manner as for the raw1156 materials.1157

14.20 The printed packaging materials must be stored under secure conditions so as to exclude1158the possibility of unauthorized access. Labels on spools must be used whenever possible.1159Split up labels and other unattached printed materials must be stored and transported in1160closed and separate containers so as to prevent their mixture. The packaging materials1161must be sent to production only through designated personnel, complying with approved1162and documented procedures.1163

14.21 Each batch of printed material and packaging material must receive a specific reference1164number or identification mark.1165

14.22 The materials that are printed, those of primary or secondary packaging, and those out of 1166date or obsolete must be destroyed and this procedure must be recorded.1167

14.23 All products and packaging materials to be used must be checked upon delivery to the1168packaging department in relation to quantity, identity and conformity with the packaging1169instructions.1170

Intermediate and bulk products1171

14.24 Intermediate and bulk products must be kept under specific conditions determined for each1172product.1173

14.25 Acquired intermediate and bulk products must be handled upon receiving as if they were1174raw materials.1175

Finished products1176

14.26 Finished products must be kept under quarantine until their final release. Subsequently,1177they must be stored as available stock, in accordance with the conditions established by the1178manufacturer.1179

14.27 The evaluation of finished products and the necessary documentation for the release of a1180product to be sold are described in section 17, “Good Quality Control Practices”.1181

Rejected, recovered, reprocessed and reworked m aterials1182

14.28 Rejected materials and products must be identified as such and stored separately, in1183restricted areas. They may be returned to the suppliers, reprocessed or destroyed. The1184action to be adopted must be approved by an Authorized Individual and duly recorded.1185

14.29 The reworking or recovery of rejected products must be an exception. This is only allowed if 1186the quality of the final product is not affected, if the specifications are complied with and if it1187is done in consonance with a defined and authorized procedure after an evaluation of the1188risks involved. A record of the reworking or recovery must be kept. A reworked batch must1189receive a new batch number.1190

14.30 The introduction of a whole or part of prior batches, in conformity with the required quality,1191into a batch of the same product at a defined manufacturing step must be authorized1192beforehand. This recovery must be done in accordance with a defined procedure after 1193evaluating the risks involved, including any possible effect on the validity term. The recovery1194must be recorded.1195

14.31 The need for additional tests on any finished product that has been reprocessed, reworked1196

or into which a recovered product has been incorporated must be considered by the quality1197 control department.1198

1199



1246Waste materials1247

14.44 Measures must be taken as to the appropriate and secure storage of the waste materials to1248be eliminated. Toxic substances and inflammable materials must be kept at locations with1249restricted access, as required by the legislation in force.1250

14.45 The waste material must not be accumulated. It must be kept in suitable containers, at a1251

specific location and must be disposed of in a secure manner and in accordance with health1252regulations, at regular and frequent intervals.1253

Various materials1254

14.46 It must not be allowed that products such as raticide, insecticide, fumigating agents and1255sanitation materials contaminate the equipment, raw materials, packaging materials,1256materials being processed or finished products.1257

15. Documentation1258

15.1 Principle. The documentation constitutes an essential part of the Quality Assurance system1259and must be related to all aspects of the GMP. It has the objective of defining the1260

specifications of all materials and manufacturing and control methods, with the purpose of 1261ensuring that all personnel involved in the manufacture know to decide what to do and1262when to do it. Besides this, it has the purpose of guaranteeing that the authorized individual1263has all of the necessary information to decide on whether to release or not a determined1264batch of medication for sale, as well as enabling tracking that will allow for investigations1265into the history of any batch that is suspected of a quality deviation. It ensures the1266availability of the necessary data for validation, review and statistical analysis. All1267documents may be placed into a single folder or kept separately, but easily available.1268

General1269

15.2 The documents must be composed, reviewed and distributed only to designated individuals.1270They must comply with all of the manufacturing steps authorized by the registration.1271

15.3 The documents must be approved, signed and dated by the designated individual. No1272document may be modified without prior authorization and approval.1273

15.4 The contents of the documents may not be ambiguous: the title, nature and objective must1274be presented in a clear, concise and correct manner. Besides this, they must be laid out in1275an orderly manner so as to be easily checked. Reproduced documents must be easily1276readable and have a guarantee as to their fidelity in relation to the original.1277

15.5 The documents must be regularly reviewed and updated. When a certain document is1278reviewed, there must be a system in place that prevents the inadvertent use of the1279substituted version. Obsolete documents must be kept for a specific period defined in a1280procedure.1281

15.6 When documents require the input of data, these data must be clear and legible, as well as1282 indelible. Sufficient space must be left for each input of data.1283

15.7 All alterations made to any document must be signed and dated; the change must enable1284the reading of the original information. When that is the case, the reason for the alteration1285must be recorded.1286

15.8 Records must be kept of all actions that are carried out or ended, in such a manner that all1287significant activities with reference to the manufacture of medications may be tracked. All1288records must be retained for at least one year after the expiry term of the finished product.1289

1290



129115.9 The data may be recorded via an electronic processing system or by photographic means1292

or by other reliable means. The master / standard formulas, as well as the Standard1293Operational Procedures – SOPs relative to the system in use, must be available, as well as1294the exactness of the checked and recorded data. If the data records are done by electronic1295processing, only designated individuals may modify the data on the computers. There must1296be records of the changes made. Access to the computers must be restricted either by the1297use of passwords or other means. The input of data considered as critical must be checked1298by another designated individual. Electronic records of the batches data must be protected1299through copies transfer onto magnetic tape, microfilm, printing on paper or other means.1300And it is particularly important that, throughout the retention period, the data are readily1301available.1302

Required documents1303

Labels1304

15.10 The identification attached to the containers, equipment, installations and products must be1305clear and without ambiguity, in a format approved by the company, containing all of the1306necessary data and, besides the text, it may contain different colors indicating its condition1307

(example: under quarantine, approved, rejected, clean).130815.11 All finished products must be identified, as required by the legislation in force, furnishing at1309

least the following information:1310

(a) medication’s name;1311(b) list of active ingredients (if there are, with the DCB), with the quantity and net content1312

(for example, number of dosage units, weight, volume);1313(c) batch number given by the manufacturer;1314(d) expiry date in a non-encoded manner;1315(e) any storage conditions or special handling precautions that may be necessary;1316(f) use instructions, as well as warnings and precautions that may be necessary;1317(g) manufacturer’s and/or outsourced and/or registration holder companies’ names and1318

addresses, as well as the Responsible Technician of the registration holder.1319

15.12 The labels for the reference standards and accompanying documents must indicate the1320concentration, manufacturing date and expiry term, the date on which the seal was broken1321and the storage conditions, as well as the control number when necessary.1322

Quality control specifications and test procedures1323

15.13 The procedures of the quality control tests described in the document must be validated1324considering the installations and the equipment available, before they are routinely adopted.1325

15.14 All specifications must be duly authorized and dated in relation to the identification, content,1326purity and quality tests on raw materials, packaging materials and finished products.1327Besides this, tests must be carried out on intermediate and bulk products, when1328appropriate. There must be specifications related to the water, solvents and reagents (acids1329

and bases) used in the production.133015.15 Each specification must be approved, signed and dated, as well as maintained by quality1331

control, quality assurance or by the documentation center.1332

15.16 Periodic reviews of the specifications must be carried out so that they can be updated1333according to the new editions of the national pharmacopoeia, or other official compendiums.1334

15.17 The pharmacopoeias, reference standards, spectrometry standards and other necessary1335reference materials must be available at the quality control laboratory.1336

Specifications fo r raw materials and packaging materials1337

15.18 The specifications for the raw materials, primary packaging materials and printed materials1338

must have a description including at least:1339(a) the name, if there is with the DCB, as well as the in-house reference code;1340(b) reference, if there is, of the pharmacopoeia monograph;1341



(c) quantitative and qualitative requirements, with the respective acceptance limits.1342

1343



1344Depending on the practice adopted by the company, other data may be added to the specifications,1345such as:1346

(a) supplier’s identification, as well as that of the original producer of the materials;1347(b) sample of the printed material;1348(c) guidelines on sampling, quality tests, and the reference used in the control1349

procedures;1350

(d) storage conditions and precautions;1351(e) maximum storage period before a new test is carried out.1352

The packaging materials must comply with the specifications, emphasizing the compatibility of such1353materials with the medication they contain. The material must be examined in relation to the1354presence of defects and correct identification marks, as well as to the required specifications.1355

15.19 The documents with a description of the control test procedures must indicate with what1356frequency new tests must be carried out on each raw material, as determined by its1357stability.1358

Specifications for intermediate and bulk products1359

15.20 The specifications for intermediate and bulk products must be available whenever these1360

materials are acquired or issued, or if the data on intermediate products have to be used in1361the evaluation of the final product. The specifications must be compatible with the1362specifications related to raw materials or finished products.1363

Specifications for fini shed products1364

15.21 Specifications for finished products must include:1365

(a) product’s generic name and brand or commercial name, when it is the case;1366(b) name(s) of the main active ingredient(s), with the respective DCB or DCI;1367(c) formula or reference to it;1368(d) pharmaceutical form and packaging details;1369(e) references used in sampling and control tests;1370

(f) qualitative and quantitative requirements, with the respective acceptance limits;1371 (g) conditions and precautions to be taken in storage, when it is the case;1372(h) validity term.1373

Master / standard formulas1374

15.22 There must be an authorized master / standard formula for each product and batch size to1375be manufactured.1376

15.23 The master / standard formula must include:1377

(a) the product’s name, with the reference code related to its tests specification;1378(b) description of the pharmaceutical form, product concentration and batch size;1379(c) list of all raw materials to be used (with their respective DCB or DCI); with the1380

quantity of each one used, using the generic name and reference, which are1381exclusive for each material. Any substance that may disappear during the course of 1382the process must be mentioned;1383

(d) statement on the final expected yield, with the acceptable limits, as well as the1384intermediate yields, when it is the case;1385

(e) indication of the processing location, as well as of the equipment to be used;1386(f) the methods (or reference to them) to be used in the preparation of the main1387

equipment, such as cleaning (especially after a change of product), assembly,1388calibration and sterilization;1389

(g) detailed instructions of the steps to be followed during production (checking of the1390materials, pretreatment, the addition sequence of materials, mixing times,1391temperatures);1392

(h) instructions related to any in-process controls, with their acceptance limits;1393

1394



1395(i) requirements related to the packaging of the products, including those on1396

containers, labeling and any special storage conditions;1397(j) any special precautions to be observed.1398

Packaging instructions1399

15.24 There must be authorized instructions as to the packaging process, related to each product1400 and to the size and type of packaging. These instructions must include the following data:1401

(a) product’s name;1402(b) description of its pharmaceutical form, its concentration and administration route,1403

when it is the case;1404(c) packaging size expressed in numerical terms, product’s weight or volume contained1405

in the final container;1406(d) complete listing of all packaging material necessary for a standard batch size,1407

including the quantities, sizes and types, with the reference code or number related1408to the specifications of each material;1409

(e) sampling or reproduction of materials used in the packaging process, indicating the1410location where they were printed or engraved, the batch number and their expiry1411date;1412

(f) special precautions must be observed, such as the careful examination of the1413equipment and of the area where packaging it is to be carried out, with the purpose1414of guaranteeing the absence of printed materials from previous products on the1415packaging lines;1416

(g) description of the packaging operations and of the equipment to be used;1417(h) details of the in-process controls, together with sampling instructions and acceptance1418

limits.1419

Batch processing records1420

15.25 Production records for each batch must be kept. These records must be based on the1421approved master / standard formula that is in use. The records must be documented so as1422to prevent errors. (The use of copies or validated computerized systems is recommended.1423

Transcriptions from approved documents must be avoided.)142415.26 Before starting a production process, it must be verified if the equipment and work location1425

are free from products that have been previously manufactured, as well as the documents1426and materials necessary for the planned process. Besides this, it must also be verified if the1427equipment is clean and suited for use. Such checks must be recorded.1428

15.27 During the production process, all of the developed steps must be recorded, contemplating1429the start and end time for the execution of each operation, and duly signed and dated by the1430individuals responsible for carrying out each step and ratified by the area supervisor. The1431production batches records must contain at least the following information:1432

(a) product’s name;1433(b) number of the batch that is being manufactured;1434(c) starting and ending dates and times of the main intermediate production steps;1435(d) name of the individual responsible for each production step;1436(e) identification of the operator(s) in the different production steps and, when1437

appropriate, of the individual(s) that check each operation1438(f) batch numbers and/or analytical control number, as well as the quantity of each raw1439

material used, including the batch number and the quantity of any recovered or 1440reprocessed material that has been added;1441

(g) any relevant operation or event that is observed during production, as well as the1442main pieces of equipment used;1443

(h) in-process controls that have been carried out, identification of the individual(s) that1444have carried them out and the results obtained;1445

(i) the quantities of product obtained in the different production steps (yield), together 1446with the comments or explanations on any significant deviation from the expected1447

yield;1448 (j) notes on special problems, including details such as the signed authorization for 1449each change in the manufacturing formula or production instructions.1450

1451



1452Batch packaging records1453

15.28 A record of the batch packaging for each processed batch must be kept, either in full or 1454partially. It must be based on the relevant parts of the approved packaging instructions and1455the preparation method of the said records must be planned so as to prevent errors. (The1456use of copies or validated computerized systems is recommended. Transcriptions from1457approved documents must be avoided.)1458

15.29 Packaging records must be kept for each batch or part thereof, in accordance with the1459packaging instructions. The records must be prepared so as to prevent transcription errors.1460

15.30 Before the start of any packaging operation, verifications must be carried out to see that the1461equipment and work stations are free from previous products, documents, or materials that1462are not required for the planned packaging operations, and that the equipment is clean and1463suited for use. Such checks must be recorded.1464

15.31 The following information must be recorded at the time that each action takes place, and1465the date and individual responsible must be clearly identified either through a signature or 1466electronic password:1467

(a) the product’s name, batch number and bulk product quantity to be packaged, as well1468

as the batch number and planned quantity of finished product that will be obtained,1469 the real quantity obtained and the reconciliation;1470(b) the packaging operations date(s) and time(s);1471(c) the name of the individual responsible for carrying out the packaging operations;1472(d) the identification of the operators in the main steps;1473(e) verifications carried out as to the identification and conformity with the packaging1474

instructions, including the results of the in-process controls;1475(f) details of the packaging operations carried out, including references to the1476

equipment and packaging lines used and, when necessary, the instructions to1477maintain the product out of its package or recording of products returned to the1478storage area, without them being packaged;1479

(g) samples of printed packaging materials used, including samples containing the1480approval for printing and regular verification (when appropriate), containing the batch1481

number, the manufacturing date, the validity term and any additional printing;1482 (h) notes on any special problems, including details surrounding any deviations from the1483furnished instructions as to the packaging process, with authorization in writing from1484the designated individual;1485

(i) the quantities of all printed packaging materials, with the reference number or 1486identification, as well as of the bulk products delivered to be packaged, used,1487destroyed or returned to stock, and the quantity of product obtained, with the1488purpose that a correct reconciliation may be carried out.1489

Standard operational procedures (SOPs) and records1490

15.32 The standard operational procedures and the records associated with the possible actions1491adopted, when appropriate, and related to the results obtained, must be available as to:1492

(a) the assembly and qualification of equipment;1493(b) the analytical apparatus and calibration;1494(c) maintenance, cleaning and sanitation;1495(d) personnel, including qualification, training, uniforms and hygiene;1496(e) environmental monitoring;1497(f) pest control;1498(g) complaints;1499(h) withdrawals;1500(i) returns.1501

15.33 There must be standard operational procedures and records for receiving raw materials and1502primary packaging materials, as well as printed materials.1503

1504



150515.34 The receiving records must include:1506

(a) material’s name, as described on the delivery note and on the containers;1507(b) in-house name and/or material code;1508(c) receiving date;1509(d) supplier’s name, as well as manufacturer’s name;1510(e) the manufacturer’s batch or reference number;1511

(f) total quantity and number of containers received;1512(g) number attributed to the batch after receiving;1513(h) any relevant comment (for example, the condition of the containers).1514

15.35 There must be Standard Operational Procedures for the in-house identification of products1515stored under quarantine and of those released (raw materials, packaging materials and1516other materials).1517

15.36 The standard operational procedures must be available for each instrument and piece of 1518equipment (for example, use, calibration, cleaning, maintenance) and placed close to the1519equipment.1520

15.37 There must be standard operational procedures for sampling and the responsible1521department, as well as the individuals authorized to collect samples, must be defined.1522

15.38 The sampling instructions must include:1523(a) the sampling method and sampling plan;1524(b) the equipment to be used;1525(c) any precautions to be observed so as to prevent contamination of the material or any1526

deterioration in its quality;1527(d) the quantity(s) of sample(s) to be collected;1528(e) instructions for any necessary subdivision of the sample;1529(f) type of container to be used in the packaging of the samples, in labeling, as well as if 1530

the sampling procedure must be carried out under aseptic conditions or not;1531(g) any precautions that must be observed, especially as to the sampling of sterile or 1532

noxious materials.1533

15.39 There must be a standard operational procedure describing the batch numbering system’s1534

details, with the objective of ensuring that each intermediate, bulk or finished product batch1535is identified with a specific batch number.1536

15.40 The Standard Operational Procedures related to the numbering of the batches that are1537applied to the packaging steps must be related one to the other.1538

15.41 The standard operational procedure for numbering the batches must ensure that the same1539batch numbers will not be used in a repeated manner, which is also applied to1540reprocessing.1541

15.42 The attribution of a batch number must be immediately recorded. The record must include1542the date on which the referred number was attributed, the identification of the product and1543the batch size. There must be written procedures related to the control tests carried out on1544the materials and products, during the different manufacturing steps, describing the1545

methods and equipment to be used. The tests that are carried out must be recorded.154615.43 The analyses records must include at least the following data:1547

(a) the name of the material or product and, when applicable, the pharmaceutical form;1548(b) the batch number and, when appropriate, the manufacturer and/or supplier;1549(c) references to the relevant specifications and test procedures;1550(d) test results, including observations and calculations, as well as references to any1551

specifications (limits);1552(e) test reference date(s) and number(s);1553(f) identification of the individuals that have carried out the tests;1554(g) identification of the individuals that have checked the tests and calculations;1555(h) statement of approval or rejection (or other decision), dated and signed by the1556

individual responsible.1557

1558



155915.44 There must be written procedures available as to the approval or rejection of materials and1560

products and, particularly, as to the release for sale of the finished product through an1561authorized individual.1562

15.45 Distribution records must be kept for each batch of a product so as to, for example, facilitate1563the withdrawing of the batch, if necessary.1564

15.46 Records must be kept on the main and critical equipment, related to any qualification,1565calibration, maintenance, cleaning or repairs, including the date and identification of the1566individuals that carried out these operations.1567

15.47 The recording of equipment use, as well as the areas in which the products are being1568processed, must be done in chronological order.1569

15.48 There must be written procedures attributing the responsibilities for cleaning and sanitation,1570and describing in details the frequency, methods, cleaning materials and equipment to be1571used, as well as the installations and equipment to be cleaned.1572

16. Good product ion practices1573

16.1 Principle. The production operations must comply with the Standard Operational1574

Procedures – SOPs, that are clearly defined and approved and in conformity with the1575 approved Technical Report as to the registration concession at the competent healthy1576authority, with the objective of obtaining products that are within the required quality1577standards.1578

General1579

16.2 All handling of materials and products, such as receiving and cleaning, quarantine,1580sampling, storage, labeling, shipping, processing, packaging and distribution must be1581carried out in accordance with written procedures or instructions and, when necessary,1582recorded.1583

16.3 Any deviation from the procedures or instructions must be prevented. In case of any1584deviations, they must be authorized and approved in writing by an individual designated for 1585the duty who is a member of Quality Assurance, with the participation of the quality control1586department when applicable.1587

16.4 Verifications must be carried out on yields and reconciliation of quantities, as necessary, to1588ensure that there are no discrepancies outside of the acceptable limits.1589

16.5 Operations with different products must not be carried out simultaneously or consecutively1590in the same room or area, unless there is no risk of mixing or cross contamination.1591

16.6 During the course of processing, all of the materials, containers with bulk, equipment and1592rooms, as well as the packaging lines used, must be identified with the indication of the1593product or material being processed, its concentration (when applicable) and the batch1594number. This indication must mention the production step. When applicable, the previously1595processed product’s name must also be recorded.1596

16.7 Access to the production installations must be restricted to authorized personnel.1597

16.8 Non-pharmaceutical products must not be produced in areas or with equipment destined for 1598the production of medications.1599

16.9 In-process controls are, most times, carried out within the production area. They must not1600present any risk to the quality of the product, with the purpose of minimizing the risks of 1601cross contamination or mixing.1602

Prevention of bacterial and cross contamination du ring production1603

16.10 When powdered materials and products are used in production, special precautions must1604be taken so as to prevent the generation and dissemination of powders. Measures must be1605

taken for the appropriate control of the air (for example, supplying and extraction of air of a1606 suitable quality).1607

1608



160916.11 The contamination of one raw material or given product by another material or product must1610

be avoided. The risk of accidental cross contamination results from the uncontrolled release1611of powders, gases, vapors, aerosols or organisms coming from the materials and products1612being processed, from residues on the equipment, from insects introduction, from the1613operators clothing and their skin, etc. The significance of this risk varies with the type of 1614contaminant and the product that was contaminated. Within the most dangerous1615contaminants are the highly sensitizing materials (e.g. penicillin, cephalosporin,1616carbapenemic, as well as other beta-lactamic derivatives), biological preparations with live1617organisms, certain hormones, cytotoxic substances and other highly active materials.1618Products whose contamination may cause greater damage to the users are those that are1619parenterally administered or applied to open wounds, as well as products administered in1620large doses and/or for long periods of time.1621

16.12 The occurrence of cross contamination must be avoided by means of the appropriate1622techniques or organizational measures, such as:1623

(a) production in exclusive and enclosed areas (which may be required for products1624such as penicillin, live vaccines, live bacterial preparations and other determined1625biological products);1626

(b) campaign production (separation for a period) followed by the appropriate cleaning,1627

in accordance with a validated cleaning procedure;1628 (c) use of antechambers, differences in pressure and air supply, as well as exhaust1629systems;1630

(d) reduction of the risk of contamination caused by the recirculation or reentry of 1631untreated or insufficiently treated air;1632

(e) use of protection clothing where the products or materials are handled;1633(f) use of validated cleaning and decontamination procedures;1634(g) use of a “closed system” of production;1635(h) tests on residues;1636(i) use of labels indicating the cleanliness condition of the equipment.1637

16.13 The efficacy of the adopted measures must be checked periodically so as to prevent cross1638contamination. This verification must be carried out in conformity with the Standard1639Operational Procedures.1640

16.14 The production areas where products that are susceptible to contamination by1641microorganisms are being processed must be monitored periodically, for example,1642microbiological and particulate material monitoring, when appropriate.1643

Production operations1644

16.15 Before any production operation is started, the necessary measures must be adopted so1645that the work areas and equipment are clean and free from any raw materials, products,1646product residues, labels or documents that are not necessary for the new operation that is1647to be initiated.1648

16.16 All in-process controls, as well as environmental controls, must be carried out and recorded.1649

16.17 Means must be instituted to indicate faults on the equipment or utilities. Faulty equipment1650 must be removed from use until it is repaired. After use, the production equipment must be1651cleaned, within the determined term and in accordance with detailed procedures. The clean1652equipment must be stored in a separate area that is clean and dry, or in a manner so as to1653prevent contamination.1654

16.18 Time limits for the equipment to remain unclean before the cleaning procedure is carried out1655and after the cleaning before it is used again must be defined. These time limits must be1656based on validation data.1657

16.19 The containers used for packaging must be cleaned before the operation. Care must be1658taken so as to prevent and to remove any contaminants, such as glass fragments and metal1659particles.1660

16.20 Any significant deviation in the expected yield must be investigated and recorded.166116.21 It must be ensured that the piping or other equipment used to transport the products from1662

one area to another is correctly connected.1663

1664



1665

16.22 The piping used to transport water for injectables and purified water or any other type of 1666water must be cleaned and sanitized, in accordance with written procedures that determine1667the microbial contamination limits and the measures to be adopted.1668

16.23 The equipment and instruments used in the measuring, weighing, recording and control1669procedures must be subjected to maintenance and calibration at pre-established intervals1670and records of the said operations must be kept. To ensure satisfactory operation, the1671instruments must be checked on a daily basis or before they are used for analytical tests.1672The calibration and maintenance dates, as well as those of when future calibrations must1673be carried out, must be clearly established and recorded, preferably on a label attached to1674the instrument or equipment.1675

16.24 Repair and maintenance operations must not present any risk to the quality of the products.1676

Packaging operations1677

16.25 In programming the packaging operations, special attention must be given to the1678procedures that minimize the occurrence of the risk of cross contamination, of mixtures or 1679substitutions. Different products must not be packaged close to one another, unless there is1680a physical separation or an alternative system that furnishes equivalent guarantee.1681

16.26 Before starting the packaging operations, measures must be taken to ensure that the work1682areas, packaging lines, printing machines and other equipment are clean and free from any1683products, materials or documents previously used and that are not necessary for the current1684operation. The releasing of the line must be carried out in accordance with the procedures1685and check list. The said verification must be recorded.1686

16.27 The name and batch number of the product being processed must be displayed in each1687packaging step or packaging line.1688

16.28 The filling and closing steps must be immediately followed by the labeling step. If this is not1689possible, then appropriate procedures must be applied so as to ensure that there is no1690mixture or labeling errors.1691

16.29 The correct printing operations performance must be checked and recorded, be they carried1692

out separately or during the packaging process. Greater attention must be given to manual1693printing, which must be checked at regular intervals.1694

16.30 With the purpose of preventing mixing / exchanging, special care must be taken when loose1695labels are used or when a large number of prints are made separately from the packaging1696line, as well as when manual packaging operations are adopted. Preferentially, labels that1697are fed from a roll, as opposed to loose labels, should be used to prevent mixtures. The line1698verification for all the labels by electronic means may be useful to prevent mixtures, but1699verifications must be carried out so as to guarantee that any electronic code readers, label1700counters or similar devices are operating correctly. When the labels are attached manually,1701in-process controls must be carried out more frequently.1702

16.31 Printed information and those in relief on the packaging materials must be clear and1703resistant to wear and adulteration.1704

16.32 The in line inspection of the product during packaging must regularly include at least the1705following verifications:1706

(a) general appearance of the packages;1707(b) if the packages are complete;1708(c) if the correct products and packaging materials are being used;1709(d) if the printing is correct;1710(e) the correct operation of the packaging line monitors.1711

Samples collected from the packaging line may not be returned.1712

16.33 Products that are involved in abnormal occurrences during the packaging procedure must1713only be reintroduced into it after being subjected to inspection, investigation and approval1714by a designated individual. Detailed records of this operation must be kept.1715

1716



171716.34 Any significant or uncommon discrepancy that is noted during the reconciliation of the1718

quantity of bulk products, printed packaging materials and the number of packaged units1719must be satisfactorily investigated and justified before the product batch is released.1720

16.35 After the conclusion of each operation, all packaging materials encoded with the batch1721number that are not used must be destroyed, with the destruction process being recorded.1722So that the non-encoded printed materials are returned to stock, the procedures in writing1723

must be followed.1724

17. Good quality cont rol practices1725

17.1 Quality control is responsible for the activities with reference to sampling, specifications and1726tests, as well as for the organization, documentation and release procedures that guarantee1727that the necessary and essential tests are carried out and that the materials are not1728released for use, nor the finished products released for sale or supply, until its quality is1729deemed to be satisfactory. Quality control must not be limited to its laboratory operations,1730but must participate and be involved in all decisions that may be related to the product’s1731quality.1732

17.2 The independence of quality control in relation to production is considered fundamental.1733

17.3 Each manufacturer (holder of a manufacturing authorization) must have a quality control1734department. This must be independent from other departments and be under the authority1735of an individual with the appropriate qualification and experience that has one or more1736control laboratories at his/her disposal. Adequate resources must be available to guarantee1737that all quality control measures are carried out with efficacy and reliability. The basic1738requirements for quality control are the following:1739

(a) adequate installations, trained personnel and approved procedures must be1740available for sampling, inspections and testing of raw materials, packaging materials1741and intermediate, bulk and finished products. When necessary, there must be1742approved procedures for environmental monitoring;1743

(b) samples of raw materials, packaging materials, intermediate, bulk and finished1744products must be collected by approved methods and by qualified personnel from1745

the quality control department;1746 (c) the necessary qualifications and validations must be carried out;1747(d) records must be kept (manually or electronically) showing that all sampling,1748

inspection and test procedures were in fact carried out and that any deviations were1749duly recorded and investigated;1750

(e) finished products must have a qualitative and quantitative composition in accordance1751with that which is described in their registration; the ingredients must have the1752required purity, they must be in appropriate containers and duly labeled;1753

(f) the results of the inspection and tests that were carried out on the materials and1754intermediate, bulk and finished products must be recorded; the product evaluation1755must include the review and analysis of the production relevant documentation, as1756well as an evaluation of the deviations from specific procedures;1757

(g) no product batch must be released for sale or distribution before it is certified by1758

authorized individual(s) that is in consonance with the specifications stated in the1759 records;1760(h) sufficient samples of raw materials and products must be withheld so as to allow for 1761

a future analysis of the product, if necessary; the withheld product must be kept in its1762final package, unless the package is exceptionally large.1763

17.4 Quality control has, as other functions, to establish, validate and implement all quality1764control procedures, evaluate, maintain and store the reference standards, guarantee the1765correct labeling of containers for materials and products, guarantee that the stability of the1766active ingredients and medications is monitored, participate in the investigation of 1767complaints related to the quality of the product and participate in the environmental1768monitoring. All of these operations must be carried out in consonance with written1769procedures and, when necessary, recorded.1770

1771



177217.5 The evaluation of finished products must cover all relevant factors, including production1773

conditions, results of in-process control, manufacturing documentation (including1774packaging), and compliance with the specifications for the finished product and an analysis1775of the final package.1776

17.6 Quality control personnel must have access to the production areas for sampling and1777investigation, if necessary.1778

Control over raw materials and intermediate, bulk and fin ished products1779

17.7 All tests must comply with the instructions established by the procedures in writing and1780approved for each material or product. The results must be checked by the supervisor 1781before the materials or products are released or rejected.1782

17.8 A sample must represent the material batch from which it was drawn, in accordance with1783written and approved procedures.1784

17.9 Sampling must be carried out so as to prevent the occurrence of contamination or other 1785adverse effects on the quality of the sampled product. The sampled containers must be1786identified and carefully closed after being sampled.1787

17.10 During sampling, care must be taken in preventing contamination or mixture of the materials1788 being sampled. All equipment used in the sampling process that comes into contact with the1789materials must be clean. Some particularly dangerous or potent materials may require1790special precautions.1791

17.11 The equipment used in sampling must be clean and, if necessary, sterilized before and after 1792its use and stored separately from all other laboratory equipment.1793

17.12 Each container containing a sample must be identified and present the following1794information:1795

(a) the name of the sampled material;1796(b) the batch number;1797(c) the number of the sampled container;1798(d) the sample number;1799(e) the signature of the individual that collected the sample; and1800(f) the sampling date.1801

17.13 Results that are out of specification obtained during the tests on materials or products must1802be investigated according to an approved procedure. The investigations must be completed1803and the corrective measures adopted. Records must be kept.1804

Necessary tests1805Raw materials and packaging materials1806

17.14 Before the raw materials and the packaging materials are released for use, the individual1807responsible for Quality control must guarantee that they are at least tested as to the1808conformity with the specifications on identification, potency, purity and other quality1809

parameters.181017.15 Identification tests must be carried out on the samples drawn from each container of raw1811

materials.1812

17.15.1 Only a part of the volumes is permitted to be sampled when a validated procedure has been1813established so as to guarantee that no volume of raw materials has been incorrectly1814labeled. The validation must take into consideration at least the following aspects:1815

a) the nature and classification by the manufacturer and supplier, as well as the degree1816of conformity with the Good Manufacturing Practices requirements;1817

b) the quality assurance system of the raw materials manufacturer;1818c) the conditions under which the raw materials are produced and controlled; and1819d) the nature of the raw materials and of the medications in which they will be used.1820

1821



1822With the said system, it is possible that a validated procedure aiming at exempting the identification1823test on all containers of raw materials may be accepted under the following cases:1824

a) raw materials originating from a monoproduction plant; or 1825b) raw materials acquired directly from the manufacturer, or from containers sealed at the1826

manufacturer, from which there is a reliable history and regular audits are carried out on the1827manufacturer’s quality assurance system or by an accredited official body.1828

This procedure is not applicable to the following cases:1829

a) raw materials supplied by intermediate parties, such as importers / distributors / splitting up1830operators;1831

b) raw materials used for parenteral products.1832

17.16 The quality of a batch of raw materials must be evaluated through tests on representative1833samples. Samples drawn for identification testing may be used for this purpose. The1834number of samples drawn to prepare a representative sample must be statistically1835determined and specified in a sampling plan. The number of individual samples that may be1836mixed to make up a composed sample must also be defined by taking into account the1837nature of the material, the supplier’s knowledge and the homogeneity of the sample’s1838composition.1839

17.17 Each batch of printed packaging material must be examined upon receiving.184017.18 The manufacturer may accept the analysis certificate issued by the supplier, as long as its1841

reliability is established through periodic validation of the presented results and through1842audits at its installations, which does not exclude the need for carrying out the identity test.1843Certificates issued by the supplier must be originals and have their authenticity assured.1844They must contain the following information:1845

(a) supplier’s identification, signature of the responsible employee;1846(b) name and number of the tested material batch;1847(c) description of the specifications and of the methods used; and1848(d) description of the test results and the date on which they were carried out.1849

In-process control1850

17.19 Records must be kept of the in-process control, which must be a part of the batch records.1851

Finished p roducts1852

17.20 Before the pharmaceutical products batches are released, it must be assured through1853laboratory tests that they comply with the established specifications.1854

17.21 Products that do not comply with the established specifications must be rejected.1855

Batch registration review1856

17.22 The production and control records must be reviewed. If it is determined that a batch does1857not comply with the specifications or if it presents any divergences, then it must be1858

investigated. If necessary, the investigation must be extended to the other batches of the1859same product or of other products that may be linked to the detected deviation. There must1860be a record of the investigation, which must contain the conclusion that was reached, as1861well as the necessary follow-up actions.1862

1863



186417.23 Samples that have been retained from each finished product batch must be retained for at1865

least twelve (12) months after the expiry date of its validity term, except for Large Volume1866Parenteral Solutions (LVPS), which must be kept for at least thirty (30) days after the expiry1867of its validity term. In general, finished products must be kept in their final packages and1868stored under the recommended conditions. If the product is packaged in large packages,1869then the samples may be exceptionally kept in smaller containers with the same1870characteristics and stored under the recommended conditions. Samples from active1871substances must be retained for at least one year after the expiry of the validity terms of the1872final product sourced from them. Samples of other raw materials (excipients), except1873solvents, gases and water, must be retained for a minimum period of two years, if the1874respective stability studies carried out by the manufacturer of the raw material allow it. The1875quantities of material samples and products retained must be sufficient to enable at least1876two full reanalyses.1877

Stability studies1878

17.24 Quality control must evaluate the quality and stability of the finished products and, when1879necessary, of the raw materials, intermediate and bulk products.1880

17.25 Quality control must establish dates and specifications for validity, based on the stability1881

tests related to the storage conditions.188217.26 A program in writing must be developed and implemented for stability studies, including the1883

following elements:1884

(a) a full description of the product involved in the study;1885(b) all methods and tests parameters, which must describe the potency, purity and1886

physical characteristics test procedures, as well as documented evidences that the1887tests carried out are indicators of the stability of the product;1888

(c) forecast as to the inclusion of a sufficient number of batches;1889(d) test schedule for each product;1890(e) instructions on special storage conditions;1891(f) instructions as to the suitable retention of samples; and1892(g) a summary of all data obtained, including the evaluation and conclusions of the1893

study.1894

17.27 The stability of a product must be determined before its commercialization and must be1895repeated after any significant changes to production processes, equipment, packaging1896materials, etc.1897

ATTACHMENT I 1898

Sterile Produc ts1899The directives herein presented do not substitute any of the prior sections, but reinforce specific points on1900the manufacture of sterile preparations, with the purpose of minimizing the risks of contamination by viable or 1901unviable particles or by pyrogenic substances.1902

1 General considerations19031.1 The manufacture of sterile preparations must be carried out in clean areas to which the entry of 1904

personnel and materials must be done through access chambers. These areas must be kept within1905the appropriate cleanliness standards and must have ventilation systems that use proven efficiency1906filters.1907

1.2 The various operations involved in preparing the materials (such as: containers and covers), in1908preparing the product, in bottleling and sterilization must be carried out in separate areas within the1909clean area. These areas are classified into four different classes (please see item 4.1 of Attachment1910I).1911

1.3 The manufacturing operations are split up into two categories: the first, in which the products are1912terminally sterilized, and the second, in which all of the process steps or part thereof are carried out1913

aseptically.1914

1915



19162 Quality Control19172.1 The samples collected for sterility testing must represent the entire batch, with special attention1918

being given to the parts of the batch that present the greatest risk of contamination, as for example:1919

(a) products that have passed through aseptic bottleling process – the samples must include the1920containers from the start and from the end of the batch, as well as after any significant1921interruption to the work;1922

(b) products that have been sterilized by heat in their final packaging – the samples must include1923packages from the potentially colder regions of the load.1924

2.2 The sterilization test carried out on the final product must be considered as only one of the last1925controls used to ensure the product’s sterility.1926

2.3 The sterility of the finished products is ensured by validation of the sterilization cycle in case of 1927terminally sterilized products, and by means of simulation with culture mediums for aseptically1928manufactured products. The batch documentation and, in case of aseptic processes, the1929environmental monitoring records must be examined in conjunction with the results of the sterility1930tests. The sterility test procedure must be validated for each product. Pharmacopoeia methods must1931be used for the validation and performance of the sterility test.1932

2.4 For injectable products, the water for the injectables, as well as the intermediate and finished1933

products, must be monitored for endotoxins, using a pharmacopoeia method that has been validated1934 for each type of product. For large volume parenteral solutions, the said monitoring of the water or 1935intermediates must also be carried out, besides the tests required by the approved monograph of the1936finished product. When a sample is rejected in a test, then the cause of rejection must be1937investigated and corrective actions adopted, when necessary.1938

2.5 Batches that are not approved in the initial sterility test may not be approved based on a second test,1939except if an investigation is carried out on the type of microorganism found, as well as on the records1940about the environmental conditions and about the processing of the batches, and the result of this1941investigation shows that the initial test was not valid.1942

3 Sanitation19433.1 Sanitation of the clean areas constitutes a particularly important aspect. These areas must be1944

frequently cleaned and sanitized, in accordance with a specific program approved by Quality1945

Assurance. The areas must be regularly monitored to detect the presence of resistant1946microorganisms. Keeping in view the limited efficacy of ultraviolet radiation, it must not be used as a1947substitute in chemical disinfection operations.1948

Table 1 – Limits for microbiological contamination1949

ClassesAir sample(CFU/m3)

Sedimentationplates

(diameter of 90mm)(CFU/4 hours)1

Contact plates(diameter of 55mm)

(CFU/plate)

Glove contact test(5 fingers)

(CFU/glove)

A < 1 < 1 < 1 < 1

B 10 5 5 5C 100 50 25 –

D 200 100 50 – 1The individual sedimentation plates may be exposed for less than 4 hours1950

3.2 The disinfectants and detergents must be monitored to detect possible microbial contamination; the1951dilutions must be kept in containers that have previously been cleaned and must not be stored for 1952long periods of time, unless they are sterilized. Partially emptied containers must not be topped up.1953The disinfectants and detergents used in the A and B classes must be sterilized before they are1954used.1955

1956



19573.3 Microbiological control must be carried out over the different classes of the clean areas during the1958

operation. When aseptic operations are carried out, then monitoring must be frequent and the1959methods, such as sedimentation plates, volumetric sampling of the air and surfaces (e.g. swab and1960contact plates), must be used. The areas must not be contaminated by the sampling methods used.1961The monitoring results must be a part of the batch documentation and reviewed for release purposes1962of the finished product. Surfaces and personnel must be monitored after carrying out critical1963operations.1964

3.4 Warning and action limits must be set to detect microbiological contamination, as well as to monitor 1965the tendency of the air quality at the installations. The limits expressed in colony forming units (CFU)1966for the microbiological monitoring of the clean areas under operation are described in Table 1.1967

4 Manufacturing of sterile preparations19684.1 The clean areas for the manufacture of sterile products are classified in accordance with their 1969

environmental conditions. Each manufacturing operation requires an appropriate environmental1970condition so as to minimize the risk of microbiological contamination as well as contamination by1971particles of the product or materials used.1972

1973

Table 2 – Air classification system for the manufacturing of sterile products according to ISO 14.644-11974

regulations1975

Degree

At rest

Maximum number of particles permitted/m3

In Operation

Maximum number of particles permitted/m3

0.5 – 5.0 µm Over 5.0 µm 0.5 – 5.0 µm Over 5.0 µm

A 3520 20 3520 20

B 3520 29 352000 2900

C 352000 2900 3520000 29000

D 3520000 29000 Not defined Not defined

1976

To achieve the “in operation” conditions these areas must be designed to achieve certain specified levels of 1977air purity in the “at rest” condition. The “at rest” condition is defined as that in which the installation is1978finalized, the production equipment is installed and operational, but there are no individuals present. The “in1979operation” condition is defined as that where the area is operational for a defined operation and with a1980specified number of people present.1981

The clean areas used in the manufacturing of sterile products are classified into four different classes, with1982these being:1983

• Class A: A high operational risk zone, for example, aseptic connections and filling. Normally these1984operations must be carried out under a laminar flow. The laminar flow systems will supply a1985homogenous air flow speed of approximately 0.45m/s ± 20% in its working position.1986

• Class B: For aseptic preparations and filling, areas surrounding the class A areas.1987

• Classes C and D: Are clean areas in which less critical manufacturing steps of sterile products1988manufacturing are carried out.1989

The classification of the air for the four classes is given in Table 2.1990• To achieve the B, C and D classes, the number of air exchanges must be appropriate to the size of 1991

the room, the equipment existing in it as well as the number of individuals working in the area. The1992number of complete air exchanges must be that of at least 20 exchanges/hour in a room with the1993standard appropriate air flow with HEPA filters.1994

1995



1996The different classification systems of particles for the clean areas are presented in Table 3.1997

Table 3 – Comparison between different classifications systems for clean areas1998

WHO (GMP) United States

(209E) United States

(usual) ISO/TC (209) EEC (GMP)

Class A M 3.5 Class 100 ISO 5 Class A

Class B M 3.5 Class 100 ISO 5 Class B

Class C M 5.5 Class 10,000 ISO 7 Class C

Class D M 6.5 Class 100,000 ISO 8 Class D

1999

4.2 The “at rest” condition as described in Table 2 must be achieved after the completion of operations,2000in the absence of personnel and after a short period of cleaning (around 15-20 minutes). The “in2001operation” condition for Class A must be maintained around the immediate surroundings of the2002product whenever it is exposed to the environment. There may be difficulty in demonstrating2003compliance with the air classification at the filling point during this operation due to the formation of 2004particles/droplets coming from the product itself.2005

4.3 It is necessary to monitor the particle levels of the clean areas during the operations.2006

4.4 Warning and action limits must be established to monitor the particles and microbiological. In case2007the limits are exceeded corrective actions must be taken in accordance with the operational2008procedures.2009

4.5 The degrees of each production area are specified in the following items and must be selected by2010the manufacturer based on the type of product and on the corresponding validations.2011

5 Fully sterilized products 20125.1 The materials and most of the products must be prepared at least within a class D environment so2013

that a low microbial and particle count may is achieved, suitable for filtering and sterilization. When2014the product is subject to a high microbial contamination risk (e.g. by being highly susceptible to2015

microbial growth it needs to be maintained for a long period of time before sterilization, or it is not2016 necessarily processed in closed containers), the preparation must be carried out in a class C2017environment.2018

5.2 The packing of fully sterilized products must be done in at least a class C environment.2019

5.3 When the product is subject to a contamination risk by the environment (e.g. slow filling process,2020containers with large openings or the exposure of these for longer than a few seconds before they2021are closed), filling must be carried out in a class A environment, surrounded by at least a class C2022area.2023

5.4 The preparation of other sterile products, that is, ointments, creams, suspensions and emulsions, as2024well as the filling of the respective containers must be carried out, generally in a grade C2025environment before final sterilization.2026

6 Aseptic preparation20276.1 The materials must be handled in at least a class D environment after being washed. The handling of 2028

sterile raw materials and materials that are not subject to sterilization or filtration must be carried out2029in a class A environment surrounded by a Class B environment.2030

6.2 The preparation of solutions that are sterilized by filtration during the process may be carried out in a2031class C area. If these solutions are not sterilized by filtration then the preparation of the materials and2032products must be carried out in a class A environment surrounded by a Class B environment.2033

6.3 The handling and packing of aseptically prepared products as well as the handling of previously2034sterilized equipment must be carried out in a class A environment, surrounded by a class B2035environment.2036

6.4 The transfer of partially closed containers, such as those used in lyophilization, must also be carried2037

out in a class A environment surrounded by a class B environment before being completely closed,2038or the transfer must occur in closed trays within a class B environment.2039

2040



20416.5 The preparation and filling of sterile ointments, creams, suspensions and emulsions must be carried2042

out in a class A environment, surrounded by a class B environment, when the product is exposed2043and later on filtered.2044

7 Manufacturing20457.1 Precautions must be taken in the sense of minimizing contamination during all of the manufacturing2046

steps, including the steps before sterilization.2047

7.2 Products of a microbiological source with live organisms cannot be manufactured or filled in areas2048that are used to manufacture other drug products. On the other hand, vaccines made with inactive2049microorganisms or with bacterial extracts may be filled, after they have been inactivated, in the same2050facilities as other drug products, as long as the inactivation and cleaning procedures are validated.2051

7.3 Validation of the aseptic processes must include the simulation of the process using a culture2052medium. The culture medium form used must generally be equivalent to the pharmaceutical form of 2053the product. The simulation process must simulate in the closest way possible the routine operations,2054including all of the subsequent critical steps. Worst case scenario must be considered in the2055simulation conditions. The simulation must be repeated at regular intervals and whenever there is2056significant change to the equipment and processes. The number of containers used in a simulation2057with a culture medium must be sufficient to validate the evaluation. For small batches the number of 2058

containers used in the simulation must be at least equal to the size of the product batch.20597.4 Caution must be exercised so that the validation processes do not negatively influence the2060

manufacturing processes.2061

7.5 Water supply sources, water treatment equipment and treated water must be regularly monitored, as2062to the presence of chemical and biological contaminants and when required, endotoxin control must2063also be carried out, so that the water complies with the appropriate specifications for its use. Records2064must be kept of the monitoring results as well as of the adopted measures.2065

7.6 Activities developed within the clean areas must be as low as possible, especially when aseptic2066operations are being carried out. The circulation of people must be methodical and controlled, with2067the purpose of preventing excessive dislodging of particles and microorganisms. The environment2068temperature and humidity must not be uncomfortably high due to the nature of the uniforms used.2069

7.7 The presence of containers and materials that generate particles in clean areas must be reduced to2070 a minimum and completely avoided when aseptic work is being carried out.2071

7.8 After the final cleaning or sterilization process, the handling of components, bulk product containers2072and equipment must be carried out in such a manner that they do not become contaminated again.2073Each step in the processing of the components, bulk product containers and equipment must be2074adequately identified.2075

7.9 The interval between washing and drying and sterilization of components, bulk products containers2076and equipment, as well as the interval between sterilization and use must be the shortest possible2077and be subject to a limit of time appropriate to validated storage conditions.2078

7.10 The time between the start of preparations of a certain solution and its sterilization or filtration by2079means of a bacterial retention filter must be the shortest possible. A maximum permissible time2080period must be established for each product that takes into consideration its composition and2081recommended storage method.2082

7.11 All the gas destined to aiding the filtration or filling process of the solution must go through the2083sterilizing filter.2084

7.12 The product bio-charge must be monitored before sterilization. A maximum contamination limit must2085be established before sterilization, which is related to the efficiency of the method that is going to be2086used and to the risk of contamination by pyrogenic substances. All solutions, especially large volume2087parenteral solutions must be filtered by sterilizing filters, and if possible immediately before its filling2088process. When aqueous solutions are placed in sealed containers the pressure compensation2089orifices must be protected, for example, with hydrophobic filters that prevent the passing of 2090microorganisms.2091

2092



20937.13 Components, bulk product containers, equipment and/or any other articles necessary in the clean2094

area where aseptic activities are being carried out, must be sterilized and whenever possible, sent to2095the clean areas via double door sterilizers built-in to the wall. Other procedures used with the2096purpose of not introducing contaminants into the clean area may be accepted under some2097circumstances (for example, triple wrapping).2098

7.14 Any new manufacturing procedure must be validated to prove its efficacy. The validation must be2099

repeated at regular intervals or when significant modifications are made to the processes or to the2100equipment.2101

8 Sterilization21028.1 Whenever possible, the products must be preferably sterilized through heat in their final container.2103

When the method of sterilization through heat is not possible due to the formulation instability then2104an alternative method must be used preceded by filtration and/or aseptic process.2105

8.2 Sterilization may be carried out by applying dry or humid heat, by ionizing radiation (but not with2106ultraviolet radiation unless the process has been carefully validated), other gaseous sterilizing agents2107or through sterilizing filtration with the subsequent aseptic filling of the final sterile containers. Each2108method has its particular applications and limitations. And whenever possible and practical the2109choice of method must be sterilization through heat.2110

8.3 The microbiological contamination of the raw materials must be kept to a minimum and the bio-2111charge must be monitored before sterilization. The specifications must include parameters for 2112assessment of the microbiological quality when the need for it has been shown through monitoring.2113

8.4 All sterilization processes must be validated considering the different charges. The sterilization2114process must correspond to that which is stated in the Product Registration Technical Report.2115Special attention must be given when sterilization methods used are not in agreement with those as2116described in the pharmacopeias or other official compendia, or when they are used to sterilize2117products that are not aqueous or simple oily solutions.2118

8.5 Before adopting any sterilization process its efficacy and suitability must be proven by physical2119measures and through the use of biological indicators in a sense that the desired sterilization2120conditions are attained at all points of each of the charge to be processed. This validation must be2121repeated at periodic intervals, at least annually, and whenever significant changes have been made2122

to the charge to be sterilized or to the equipment. The results must be recorded.2123

8.6 For effective sterilization all material must undergo the required treatment and the process must be2124planned so as to ensure its effective sterilization.2125

8.7 The biological indicators must only be considered as an additional monitoring method of the2126sterilization processes. They must be stored and used in accordance with the manufacturer 2127instructions and their quality checked through positive controls. If these are used then strict2128precautions must be taken to prevent microbial contamination from these.2129

8.8 Clear means for differentiating products and materials that have been sterilized from those that have2130not must be established. Each container, tray or other type of product or material transporter must be2131visibly identified with the name of the material or product, its batch number and an indication if it has2132been sterilized or not. When appropriate, indicators may be used such as autoclave tape to indicate2133

if a certain batch (or sub-batch) has undergone the sterilization process or not. However, these types2134 of indicators do not provide reliable information to prove that in fact the batch has been sterilized.2135

8.9 Records must be kept for each sterilization cycle. These must be approved as a part of the batch2136release procedure.2137

9 Sterilization through heat21389.1 Each sterilization cycle through heat must be recorded with the appropriate equipment with suitable2139

precision and reliability, (for example: a graph of time/temperature with a sufficiently broad scale).2140The temperature must be recorded from a probe installed in the coldest spot of the sterilization2141chamber, such point has been determined during the qualification process. The temperature must be2142checked preferably against an independent temperature sensor located in the same position. The2143sterilization cycle records must become a part of the batch documentation. Chemical and biological2144

indicators may also be used but these must not substitute physical controls.21452146



21479.2 Sufficient time must be given so that the entire load reaches the necessary temperature before time2148

and sterilization measurements are started. This time must be determined for each type of load2149being processed.2150

9.3 After the maximum temperature phase of the sterilization cycle through heat, the necessary2151precautions must be taken to prevent contamination of the sterilized load during the cooling phase.2152Any fluid or gas used in the cooling phase that comes in contact with the product must be sterilized.2153

10 Sterilization through damp heat215410.1 Sterilization through damp heat is recommended in case of materials permeable to water vapor and2155

aqueous solutions. Temperature and pressure must be used to monitor the process. The2156temperature recording probe must be independent from the probe used in the autoclave controller 2157and there must be a temperature indicator whose reading during the sterilization process must be2158routinely checked, by comparing the values obtained on the graph. In case of autoclaves that have a2159drain on the lower part of the sterilization chamber it is also necessary to record the temperature in2160this position during the entire sterilization process. When a vacuum phase is a part of the sterilization2161cycle periodic checks of the chamber hermetical sealing must be carried out.2162

10.2 Materials to be sterilized (when they are not products contained in sealed containers) must be2163wrapped in materials that allow for the removal of air and the penetration of vapor and still prevent2164

recontamination after sterilization. All parts of the autoclave load must be in contact with the2165 saturated vapor or with the water, at the temperature required during the entire stipulated time.2166

10.3 It must be ensured that the vapor used in sterilization is of a suitable quality for the process and that2167it does not contain additives in quantities that may cause contamination of the product or equipment.2168

11 Sterilization through dry heat216911.1 Sterilization through dry heat may be suited to non-aqueous liquids or powdered products. The2170

sterilization process through dry heat must include the forced circulation of air within the sterilization2171chamber as well as maintaining a positive pressure with the purpose of preventing the entry of 2172unsterilized air. If air is forced into the chamber then this air must be filtered through a sterilizing2173filter. When the sterilization process through dry air is also used for the removal of pyrogens then2174tests that use endotoxins must be carried out as part of the validation.2175

12 Sterilization through radiation217612.1 Sterilization through radiation is mainly used in materials that are sensitive to heat. On the other 2177

hand many drug products and some packaging materials are sensitive to radiation. Therefore this2178method must only be applied when there are no noxious effects to the product, experimentally2179proven. Ultraviolet radiation is not an acceptable method of sterilization.2180

12.2 If sterilization through radiation is carried out by a third-party contract then the manufacturer is2181responsible for ensuring that the requirements as provided for in the previous item are complied with2182and that the sterilization is validated. The responsibilities of the radiation plant operator (e.g. using2183the correct dosage) must be specified.2184

12.3 During the sterilization process the radiation doses used must be measured. For this purpose2185dosage meters must be used that are independent from the quantity of the applied dosage and that2186indicate the real quantity of radiation doses received by the product. The dosage meters must be2187included with the load in sufficient numbers and as close to one another so that it can be assured2188that there is always a dosage meter in the radiation chamber. When plastic dosage meters are used2189they must be used within the established time limit after its calibration. Equally the reading of the2190values must be carried out as close as possible to the radiation point. Biological indicators may only2191be used as an additional means of control. Colored disks that are sensitive to radiation may be used2192to differentiate the packages that have undergone radiation, from those that have not; but cannot be2193considered as indicators in assuring sterility. All information obtained during the process must be2194recorded in the batch documentation.2195

12.4 The validation methods for the processes used must ensure that the effects of the variation of 2196densities of the packaging materials have been considered.2197

12.5 The procedures for handling materials must ensure that there is no possibility of mixing the irradiated2198

products with those that have not been irradiated. Each package must have an indicator that is2199 sensitive to radiation to identify that it has been irradiated.2200

12.6 The full radiation dose must be applied for a preestablished period of time.2201

2202



220313 Sterilization through fumigants and gases220413.1 This method of sterilization must only be used when there is no other viable method.2205

13.2 Various gases and fumigants may be used for sterilization (e.g. ethylene oxide, hydrogen peroxide2206vapors). The ethylene oxide must only be used when there is no other applicable method. During the2207validation process it must be proven that there are no noxious effects for the product and that the2208ventilation time is sufficient so that the gas and reactive product residues are below the limit that is2209

defined as acceptable for the product. These limits must be incorporated into the specifications.221013.3 It is essential for there to be direct contact between the gas and the microorganisms. Precautions2211

must be adopted so as to prevent the presence of organisms that may be contained in the materials2212such as crystals or dried protein. The nature and quantity of the packaging materials may2213significantly affect the process.2214

13.4 Before undergoing the action of the gas the materials must reach and maintain the equilibrium with2215the temperature and humidity as required by the process. The time used in this process must be2216considered so as to minimize the time before sterilization.2217

13.5 Each sterilization cycle must be monitored with suitable biological indicators, an appropriate number 2218of these must be used, distributed throughout the load. The information thus obtained must be a part2219of the batch documentation.2220

13.6 The biological indicators must be preserved and used in accordance with the manufacturer 2221instructions and their performance must be checked by means of positive controls.2222

13.7 For each sterilization cycle records must be kept of the sterilization cycle time period, pressure,2223temperature and humidity within the chamber during the process as well as the gas concentration.2224The pressure and temperature must be recorded on a graph throughout the cycle. The records must2225be a part of the batch documentation.2226

13.8 After sterilization the load must be stored in a controlled manner, under ventilation conditions so that2227the presence of residual gas in the reactive products drops to acceptable levels. This process must2228be validated.2229

14 Aseptic process and sterilization through filtration223014.1 The objective of the aseptic process is to maintain sterility of a product that is prepared from the2231

components that were sterilized by one of the abovementioned methods.2232

14.2 The operating conditions must prevent microbial contamination.2233

14.3 During the aseptic process special attention must be given to the following items so as to maintain2234the sterility of the components and products:2235

(a) the environment;2236(b) the personnel;2237(c) the critical surfaces;2238(d) sterilization procedures and the transfer of containers/lids2239(e) the maximum storage period of the product before it is filled, and2240(f) the sterilizing filter.2241

14.4 Certain solutions and liquids that cannot be sterilized in their final containers may be filtered into2242previously sterilized containers, through the use of sterile filters, which have a nominal pore size of 22430.22 µm (or smaller) or that have similar properties for retaining microorganisms. Said filters may2244remove bacteria and fungi, but not all viruses or mycoplasmas. Complementing the filtration process2245with some heating phases is a possibility that must be considered.2246

14.5 Due to the additional potential risks of the filtration method when compared with other filtration2247processes it is recommended that a double layer filter be used or an additional filtration immediately2248before filling. The final sterilizing filtration must be carried out as close as possible to the filling point.2249

14.6 Filters that release fibers must not be used. The use of filters that use asbestos must be absolutely2250excluded.2251

2252



225314.7 The integrity of the filter must be checked through an appropriate method, such as the “bubble point”2254

test, diffusive flow or pressure retention test, immediately after use. It is also recommended that the2255filter integrity test be carried out before use. The time spent to filter a known volume of a given2256solution and the difference in pressure used must be determined during the validation process. Any2257significant differences in relation to the established parameters must be recorded and investigated.2258The results of these checks must be written down in the batch documentation. The integrity of the2259critical gas and air filters must be confirmed after use. The integrity of the other filters must be2260confirmed at appropriate intervals. The increase in monitoring of the integrity of filters in processes2261that involve drastic conditions must be considered, as for example, the circulation of air at high2262temperature.2263

14.8 The same filter must not be used for longer than one work day unless the said use has been2264validated.2265

14.9 The filter must not affect the product, removing its ingredients or adding other substances.2266

15 Personnel226715.1 Only the minimum number of required individuals must be present in the clean areas; this is2268

particularly important during the aseptic processes. If possible the inspections and controls must be2269carried out on the outside of these areas.2270

15.2 All personnel (including cleaning and maintenance) that carry out activities within these areas must2271receive initial and regular training in matters that are relevant to the manufacturing of sterile2272products, including the reference to questions of personal hygiene and the basic concepts of 2273microbiology. In case it becomes necessary for individuals that have not received training to enter 2274these areas (that is, individuals that have been hired for construction or to carry out maintenance),2275specific precautions must be taken as to the supervision of these.2276

15.3 Employees that are participating in activities related to the production of products on animal tissue2277substrates or the culturing of microorganisms different from those used in the manufacturing process2278in progress must not enter the production area of sterile products, unless previously established2279decontamination procedures are applied.2280

15.4 The adoption of high standards of personal hygiene and cleanliness is essential. Individuals involved2281in the manufacturing of drug products must be instructed to notify their supervisor of any change to2282

their health condition that may contribute to the dissemination of contaminants. It is recommended2283that periodic health check-ups be carried out. The actions to be taken in relation to individuals that2284may be introducing undue microbiological risks must be taken by competent personnel designated2285for such.2286

15.5 Personal clothing must not be brought into the clean areas. Individuals that enter the dressing rooms2287of these areas must already be dressed in the company standard uniforms. The clothing change and2288hygiene processes must follow written procedures, prepared to minimize contamination of the clean2289gearing area, or the carrying of contaminants to the clean areas.2290

15.6 Wrist watches and jewelry must not be worn in the clean areas as well as cosmetic products that2291may release particles.2292

15.7 The clothing used must be appropriate to the process and the classification of the clean area where2293

the personnel are working, with the following being observed:2294Grade D: Hair, beards and moustaches must be covered. Protective clothing and appropriate footwear or 2295

footwear protectors for the area must be worn. Appropriate measures must be taken so as to2296prevent any contamination coming from outside areas.2297

Grade C: Hair, beards and moustaches must be covered. The appropriate clothing must be worn, tied at2298the wrist and with a high collar. The clothing may not release fibers or particles. Besides,2299appropriate footwear or footwear protectors must be worn.2300

Grades A/B: Hoods must be worn that completely cover the hair, beard or moustache, the lower edges of 2301these must be tucked inside the clothing. Face masks must be worn so as to prevent2302perspiration drops from being spread. Sterilized rubber gloves must be worn, without powder,2303as well as disinfected or sterilized boots. The hems of the pants must be tucked inside the2304

boots as well as the sleeves must be tucked inside the gloves. The protective clothing must not2305 release any particles or fibers shed by the body of the individual wearing it.2306

2307



230815.8 Personal clothing must not be brought into the gearing room areas that have access to the grade B2309

and C areas. All employees that are working in grade A or B areas must receive clean and sterilized2310clothing for each work session. The gloves must be regularly disinfected during the operations, as2311well as the gloves and masks being changed at each new work session. The use of disposable2312clothing may be necessary.2313

15.9 Clothing used in the clean areas must be washed and clean, so as to prevent the release of 2314

contaminants in the areas in which they will be used. It is recommended that a laundry destined2315exclusively for this type of clothing be setup. Clothing that is damaged through wear may increase2316the risk of releasing particles. The cleaning and sterilizing operations must follow the Standard2317Operational Procedures – SOPs.2318

16 Facilities231916.1 Whenever possible all facilities must be designed so as to prevent the unnecessary entry of 2320

supervision and control personnel. The grade B areas must be designed so as that all operations2321may be watched from the outside.2322

16.2 Within the clean areas all exposed surfaces must be smooth, impermeable, in order to minimize the2323accumulation or release of particles or microorganisms, allowing for the repeated application of 2324cleaning and disinfecting agents, when required.2325

16.3 To reduce the accumulation of dust and to facilitate cleaning there may be no surfaces within the2326clean areas that may not be cleaned. Facilities must have minimum protrusions, shelves, cupboards2327and equipment. The doors must be built so as to prevent having surfaces that cannot be cleaned;2328sliding doors must not be used.2329

16.4 The ceilings must be sealed so that contamination coming from the space above these may be2330prevented.2331

16.5 The piping and ducts as well as other utilities must be installed so that they do not create spaces that2332are difficult to clean.2333

16.6 Washbasins and drains must be avoided whenever possible and these must not exist in A/B areas2334where aseptic operations are carried out. When these need to be installed they must be designed,2335located and maintained in a manner so as to minimize microbial contamination risks, these must2336

have efficient siphons that are easy to be cleaned and adequate so as to prevent refluxes of air or 2337 liquids. Channels on the ground, if they are present, must be open and easy to clean and be2338connected to external drains so that the introduction of microbial contaminants is avoided.2339

16.7 The dressing rooms within the clean areas must be designed as closed antechambers and used so2340as to allow for the separation of the different stages and changes in clothing, thus minimizing2341microbial and particulate contamination arising from the protection clothing. Besides, the dressing2342rooms must have filtered air blown in an efficient manner. The use of separate dressing rooms for 2343entry and exits may be necessary on some occasions. Facilities destined for the cleaning of hands2344must be located only in the dressing rooms, never in locations where aseptic operations are carried2345out.2346

16.8 Both doors to the antechambers may not be opened simultaneously, and there must be a system in2347place that prevents this. There must be an audible and/or visual alarm system that warns of the2348

condition.234916.9 The clean areas must have a ventilation system that blows filtered air and that maintains a positive2350

pressure of the area in relation to the surrounding zones. Ventilation must be efficient and suitable to2351the required conditions. The adjacent rooms of different grades must have a differential pressure of 2352approximately 10 - 15 Pascal (reference value). Special attention must be given to the zones with2353greatest risk, where the filtered air comes in contact with the clean products and components. It may2354be necessary that the various recommendations in relation to the supply of air and the pressure2355differentials be modified in case it is necessary to contain pathogenic, highly toxic and radioactive2356materials or live viruses or bacterial materials. In some processes it may be necessary to use2357facilities destined for decontamination and treatment of the air that is exiting the clean area.2358

16.10 It must be shown that the air system does not constitute a risk of contamination. It must be assured2359that it does not allow the dissemination of particles originating from individuals, equipment or 2360

operations into the production zones with greater risk.23612362



236316.11 An alarm system must be installed so as to indicate the occurrence of failures in the ventilation2364

system. In addition, a pressure differential indicator must be placed between the areas where the2365said difference is important. The differences in pressure must be recorded regularly.2366

16.12 Unnecessary access of individuals and materials must be avoided to the critical areas. Whenever 2367necessary, access must be carried out by means of physical barriers.2368

17 Equipment236917.1 Conveyor belts must not be used to connect clean grade A or B areas and areas that present a lower 2370

air classification, unless the conveyor belt is continuously sterilized (for example: a sterilizing tunnel).2371

17.2 Whenever possible, the equipment used in the manufacturing of sterile products must be chosen in a2372way they can be sterilized by vapor, dry heat or some other method.2373

17.3 Whenever possible, the availability of the equipment and utilities must be designed and installed so2374that the maintenance and repair operations may be carried out on the outside of the clean areas.2375The equipment that must be removed for maintenance must be sterilized after being reassembled.2376

17.4 When equipment maintenance is carried out inside the clean areas, the tools and equipment must2377also be cleaned and disinfected. If the required cleanliness and/or asepsis standards are not met2378during the maintenance service then the areas must be disinfected so that production may be2379

resumed.238017.5 All equipment including sterilizers, air filtering systems, and water producing systems must undergo2381

a periodic maintenance, validation and monitoring plan. The approval of the use of the equipment2382must be documented after the maintenance service.2383

17.6 The water treatment and distribution installations must be designed, built and maintained so as to2384ensure the reliable production of water of an appropriate quality. The system must not be operated2385beyond its installed capacity. Consideration must be given, including a monitoring program, to the2386maintenance of the water system. Water for injectables must be produced, stored and distributed as2387to prevent the growth of microorganisms, for example, through constant circulation at a temperature2388of over 70º C or at not more than 4º C.2389

18 Finalizing the manufacturing steps2390

18.1 The containers must be sealed by suitable and duly validated procedures. Samples must be2391 controlled in relation to their integrity according to established procedures. In the case of vacuum2392sealed containers the samples must be controlled to check that the vacuum is maintained according2393to the predetermined period of time.2394

18.2 The final containers that contain parenteral products must be individually inspected. If the inspection2395is visual it must be carried out under adequate and controlled lighting and contrast conditions.2396Operators destined to this work must undergo periodic visual acuity tests, considering corrective2397lenses if required, and have frequent rest periods during the work period. If other inspection methods2398are used, the process must be validated and the equipment reliability must be checked periodically.2399The results must be recorded.2400

19 Isolator technology240119.1 The use of isolating technology to minimize human intervention in the production areas may result in2402

a significant decrease to the risk of microbiological contamination coming from the environment in2403aseptically prepared products.2404

19.2 The input and withdrawing of materials from the isolator is one of the main sources of contamination.2405

19.3 The classification of the air required for the environment surrounding the isolator depends on its2406design and its application. The surrounding environment must be controlled and for aseptic2407processes there must be a minimum of grade D classification.2408

19.4 Isolators may only be used after validation. The validation must consider all critical factors of the2409isolator technology, as for example, the internal and external quality of the isolator, sanitation, and2410material transfer process and isolator integrity.2411

19.5 Monitoring must be carried out routinely and must include leak tests on the isolator and on the2412

gloves/sleeves.2413

2414



241520 Blow / Fill / Seal Technology241620.1 The blowing/filling/sealing technologies are equipment for continuous operation so as to form2417

containers from thermoplastic granules and to fill and seal. Blowing/filling/sealing equipment used in2418aseptic operations, which have a grade A air blowing system, may be installed in at least a grade C2419environment, as long as clothing for grade A/B are worn. The environment must comply with the2420viable and non-viable particulate limits. The blowing/filling/sealing equipment used in the2421manufacture of fully sterilized products must be installed in at least a grade D environment.2422

20.2 At least the following parameters must be checked:2423

(a) equipment design and qualification;2424(b) validation and reproducibility of the cleanliness at the location as well as location sterilization;2425(c) cleanliness classification of the area in which the equipment is installed;2426(d) operator training and clothing;2427(e) interventions in the equipment critical zones, including any aseptic assembly prior to the start2428

of filling operations.2429

ATTACHMENT II 2430

Biological products2431

1 Scope24321.1 The objective of this chapter is to complement the "Good Manufacturing Practices of Drug Products"2433

reinforcing the specific points on the manufacturing of biological products.2434

1.2 The regulatory procedures necessary to control the biological products are mostly determined by the2435origin of the products as well as by the manufacturing technologies used. The manufacturing2436procedures contained in these regulations include: the growth of microorganism strains as well as2437that of eukaryotic cells; and the extraction of substances from biological tissues or fluids of human,2438animal or vegetable origin (allergenic); recombinant DNA technique (rDNA); hybridoma technique;2439multiplication of microorganisms in embryos or on animals.2440

1.3 Biological products manufactured with these techniques include allergenics, antigens, vaccines,2441hormones, cytokines, enzymes, human plasma derivatives, hyperimmune sera (heterologous),2442

immunoglobulin (including monoclonal antibodies), fermentation products (including products2443 derivative from rDNA) and diagnostic agents for “in vitro” use.2444

2 General considerations24452.1 The manufacturing of biological products must be carried out in accordance with the principles of 2446

Good Manufacturing Practices (GMP). As a result, the points handled in this ATTACHMENT, which2447are considered complementary to the “Good Manufacturing Practices of Drug Products" and are2448specifically related to the production and quality control of biological drug products.2449

2.2 The manner in which the biological products are produced, inspected and administrated calls for 2450certain special precautions. Contrary to the conventional pharmaceutical products that are normally2451manufactured and controlled by reproducible chemical and physical techniques, biological products2452are manufactured with technologies that involve biological processes and materials, which are not2453always reproducible.2454

2.3 The biological product manufacturing processes have an intrinsic variability and therefore2455degradation and the nature of the sub-products are not constant. It is for this reason that in the2456manufacturing of biological products it is even more critical to comply with the recommendations2457established by the GMP, during all manufacturing phases.2458

2.4 The quality control of biological products almost always implies the use of biological techniques that2459have greater variability than the physical-chemical determinations. Control during the process2460acquires great importance in the manufacturing of biological products because certain quality2461deviations are not detected during the quality control assays carried out on the finished product.2462

2463



24643 Personnel24653.1 During the work period the personnel must not walk through the areas where microorganisms or live2466

animals are handled for the facilities where work is carried out with other products or organisms,2467unless defined decontamination measures are applied, including the change of uniforms and2468footwear.2469

3.2 Personnel assigned to production must be separate from the personnel responsible for taking care of 2470

the animals.24713.3 All personnel involved either directly or indirectly in manufacturing, maintenance, control and animal2472

rooms must be vaccinated with specific vaccines and, when necessary, undergo periodic tests to2473detect any signs of infectious contagious diseases.2474

3.4 When BCG vaccines are manufactured, access to the production areas must be restricted to the2475personnel who are carefully monitored through periodic medical examinations.2476

3.5 In case of manufacturing of human blood or plasma derivatives the personnel must be immunized2477with vaccine against hepatitis B.2478

4 Facilities and Equipment24794.1 Dissemination through air of pathogenic microorganisms handled during manufacturing must be2480

prevented.24814.2 Areas used for work on animal tissues and microorganisms that are not used in the manufacturing2482

process as well as for tests carried out on animals or microorganisms must be separate from the2483facilities used in the manufacturing of biologically sterile products, with independent ventilation2484systems and different personnel.2485

4.3 In the areas used in the manufacturing of campaign products the design of the facilities and the2486equipment placement must allow for rigorous cleaning and sanitation after manufacturing, and when2487necessary, effective decontamination through sterilization and/or fumigation. All processes used2488must be validated.2489

4.4 Live microorganisms must be handled in equipment and with procedures that ensure maintaining the2490culture purity, as well as protecting the operator from contamination with said organism.2491

4.5 Biological products such as vaccines with dead microorganisms, toxoids, bacterial extracts, including2492 preparations through recombinant DNA techniques, may, once inactive be bottled in the same2493installations used for other sterile products, as long as suitable decontamination measures are taken2494after filling, including, cleaning and sterilization.2495

4.6 Biological products coming from sporulated microorganisms must be handled in exclusive facilities2496for this group of products, until the inactivation process is terminated. When it is Bacillus anthracis,2497Clostridium botulinum and Clostridium tetani, isolated and exclusively dedicated facilities must be2498used, for each of these products.2499

4.7 When inside facilities or set of facilities where preparations with sporulated microorganisms for a2500campaign production are carried out, then only one product must be produced at a time.2501

4.8 The steps up to the viral inactivation in the manufacturing of human blood or plasma derivative2502products must be carried out in facilities and equipment exclusively destined for this purpose. But,2503once they are inactive they may be bottled in the same facilities used for other sterile products, as2504long as adequate measures are taken to decontaminate after filling, including cleaning and2505sterilization. All processes used must be validated and the risk must be evaluated.2506

2507



25084.9 Crosscontamination must be prevented by adopting the following measures, when applicable:2509

(a) carry out the manufacturing and filling in segregated areas;2510(b) avoid the production of different products at the same time, unless these are in effectively2511

physically separate areas;2512(c) transfer biological materials safely;2513(d) change clothing when entering different production areas,2514

(e) carefully clean and decontaminate the equipment;2515(f) take precautions against the risk of contamination caused by recirculating air within the clean2516

environment or through the accidental return of the expelled air;2517(g) use "closed systems" in production;2518(h) take precautions to prevent the formation of aerosols (especially through centrifuging and2519

mixtures);2520(i) prohibit the entry of samples of pathological specimens not used in the production process in2521

areas used for the production of biological substances;2522(j) use sterilized containers and when appropriate, containers with a documented low microbial2523

charge.2524

4.10 The preparation of sterile products must be carried out in a clean area with a positive air pressure.2525But, all organisms considered pathogens must be handled with a negative air pressure and in2526

especially reserved locations for this purpose in accordance with the isolation regulations for the2527 product in question.2528

4.11 Areas in which pathogenic microorganisms are handled must have an exclusive air circulation2529system and it must not be recirculated. The air must be expelled through sterilizing filters whose2530operation and efficiency must be periodically checked. The filters used must be incinerated after they2531are used.2532

4.12 When used in the manufacturing of pathogenic microorganism products the production area must2533have specific decontamination systems of the effluent.2534

4.13 The ventilation piping, valves and filters for the equipment must be designed so as to facilitate its2535cleaning and sterilization.2536

4.14 The ventilation filters must be hydrophobic and must be ventilated for its proposed use.2537

4.15 Small quantities of substances to be used may be kept in the production areas during the production2538process, as long as they are not returned to storage.2539

5 Animal facilities25405.1 The animals employed in production and quality control must be housed in independent facilities2541

from the other areas of the company, with independent ventilation systems.2542

5.2 The design of the facilities as well as the construction materials used must allow for the maintenance2543of the area under hygienic conditions and have protection against insects and other animals.2544

5.3 Personnel working with animals must wear clothing exclusive to the area.2545

5.4 The facilities for taking care of the animals must include an isolation area to quarantine animals that2546enter it as well as an area to store food.2547

5.5 The animal inoculation area must be separate from the one destined for carrying out necropsy.2548

5.6 There must be a facility to disinfect the cages and if possible with vapor sterilization.2549

5.7 It is necessary to control and register the health conditions of the animals used.2550

5.8 Special precautions are necessary when monkeys are used in production or quality control.2551

5.9 Excrement and animal cadavers must be safely eliminated, decontaminated through sterilization and2552if possible incinerated.2553

2554



26043.2 Scope of validation2605

3.2.1 There must be a sufficient and appropriate system, including organizational structure and2606documentation, sufficient personnel and financial resources to carry out the validation within2607the anticipated deadline. Management and the individuals responsible for the Quality2608Assurance must be involved.2609

3.2.2 Personnel with the appropriate experience and qualifications must be responsible for 2610

carrying out the validation. They must represent the different departments depending on the2611validation work to be carried out.2612

3.2.3 There must be good preparation and planning before carrying out the validation. There must2613be a specific program for the validation activities.2614

3.2.4 Validation must be carried out in a structured manner and in accordance with documented2615procedures and protocols.2616

3.2.5 Validation must be carried out for:2617

– new facilities, equipment, utilities and systems, processes and procedures;2618 – at periodic intervals; and2619 – when large scale changes are made.2620

(Periodic requalification or revalidation may be substituted, where appropriate, with periodic2621 evaluation of the data and information to establish if the requalification or revalidation is necessary).2622

3.2.6 The validation must be carried out in accordance with the written protocols. At the end a2623validation report must be drawn up.2624

3.2.7 The validation must be carried out over a period of time, for example, at least three2625consecutive batches (industrial scale) must be validated to show the consistency of the2626process. “Worst case scenario” conditions must be considered.2627

3.2.8 There must be a clear distinction between in-process control and validation. In-process2628controls are tests that are carried out during the production of each batch in accordance with2629the specifications and methods as established in the developmental phase. The objective is2630to continuously monitor the process.2631

3.2.9 When a new formula or manufacturing method is adopted, measures must be taken to show2632 its suitability to the routine process. The defined process using specified materials and2633equipment must show results of consistent yields of a product with the required quality.2634

3.2.10 The manufacturers must identify what is necessary to validate and prove that the critical2635aspects of their operations are under control. Significant changes to the facilities, equipment2636and processes that may affect the quality of the product must be validated. A risk evaluation2637must be used to determine the scope and the extent of the validation.2638

4. Qualification26394.1 The qualification must be complete before the validation is carried out. The qualification process2640

must be constituted of a systematic and logical process, as well as being started with the design2641phases of the facilities, equipment and utilities.2642

4.2 Depending on the equipment function and operation, utility or system under certain conditions, only2643facilities qualification (FQ) will be necessary and operation qualification (OQ), as well as the correct2644operation of the equipment, utilities or systems may be considered as a sufficient indicator of its2645performance (PQ). The equipment, utilities and systems must be periodically monitored and2646calibrated, besides being undergoing preventive maintenance.2647

4.3 The main pieces of equipment as well as the utilities and critical systems do nevertheless need the2648installation qualification (FQ), operation (OQ) and performance (PQ).2649

2650



26515. Calibration and verification26525.1 The calibration and verification of the equipment, instruments and other devices, when applicable,2653

used in production and quality control, which must be carried out at regular intervals.2654

5.2 The personnel responsible for carrying out calibration and preventive maintenance must have the2655appropriate training and qualification.2656

5.3 A calibration program must be available and must provide information such as calibration standards2657and limits, responsible individuals, calibration intervals, records and actions to be taken when2658problems are identified.2659

5.4 The standards used for calibration must be traceable to the Rede Brasileira de Calibração – 2660(Brazilian Calibration Network).2661

5.5 The equipment, instruments and other devices that are calibrated must be labeled, and encoded or 2662somehow identified so as to indicate their calibration status as well as the date for the next2663calibration.2664

5.6 When the equipment, instrument or other device is not used for a certain period of time its2665functioning and calibration must be checked to be shown to be satisfactory before being used.2666

6. Master Validation Plan2667

6.1 The MVP must contain the key elements for the validation program. It must be concise and clear as2668well as have at least the following:2669

• A Validation Policy;2670• Organizational Structure of the validation activities;2671• Summary/List of the facilities, systems, equipment and processes that are found to be2672

validated as well as those that must be validated (current condition and program);2673• Models of documents (e.g.: protocol and report models);2674• Planning and Schedule;2675• Change Control;2676• Cross references.2677

7. Qualification and validation protocols2678

7.1 There must be qualification and validation protocols that describe the studies to be carried out.26797.2 The protocols must include at least the following information:2680

– the study objectives;2681 – the location/plant where the study is to be conducted;2682 – individuals in charge;2683 – description of the procedures to be adopted;2684 – equipment to be used, standards and criteria for relevant products and processes;2685 – type of validation;2686 – the processes and/or parameters;2687 – sampling, monitoring tests and requirements;2688 – acceptance criteria.2689

7.3 There must be a description as to how the results are to be analyzed.2690

7.4 The protocol must be approved before the validation itself is started. Any change to the protocol2691must be approved before being adopted.2692

8. Qualification and validation reports26938.1 Reports must be drawn up on the qualifications and validations that have been carried out.2694

8.2 The reports must reflect the protocols that have been followed and contemplate at least the title,2695study objective, as well as making reference to the protocol, details on the materials, equipment,2696programs and cycles used, as well as the procedures and methods that were used.2697

8.3 The results must be evaluated, analyzed and compared with the previously established acceptance2698criteria. The results must comply with the acceptance criteria. Deviations and results that are outside2699the limits must be investigated by the company. If the deviations are accepted, then they must be2700

justified. When necessary, additional studies must be carried out.2701

2702



28402.3 Water for injectables2841

2.3.1 The water for injectables must comply with pharmacopeia specifications as to its2842chemical and microbiological purity.2843

2.3.2 The water for injectables must be used in the preparation of sterile products. The2844water for injectables must also be used as the final rinsing water after cleaning the2845

equipment and components that come in contact with sterile products.28462.3.3 The vapor, when it comes in contact with a sterile product in its final container or in2847

equipment for the preparation of sterile products, must comply with the2848specifications for water for injectables, when condensed.2849

3 Water purif ication methods2850

3.1 General considerations2851

3.1.1 The method chosen for water purification or sequence of purification steps must be2852appropriate to the application in question. The following items must be considered2853when selecting the water treatment method:2854

– water quality specification;2855 – the result or efficiency of the purification system;2856 – the quality of the supply water as well as the seasonal changes;2857 – the reliability or robustness of the water treatment equipment in operation.2858

3.1.2 The specifications for the water purification equipment, storage and distribution2859systems must consider the following items:2860

– risk of contamination arising from leaching from the materials it comes in contact2861with;2862

– the adverse impact of absorbable contact materials;2863 – design that allows for the cleaning of the system when required;2864 – resistance to corrosion;2865 – free from leaks;2866 – configuration so as to prevent microbiological proliferation;2867 – tolerance to cleaning and sanitation agents (thermal and chemical);2868 – system capacity and production requirements; and2869 – the installation of all instruments, necessary sampling points so as to allow all2870

critical parameters of the system to be monitored.2871

3.1.3 The design and configuration as well as the layout of the water purification2872equipment as well as of the storage and distribution systems must consider the2873following physical considerations:2874

– space available for installation;2875 – structural loads on buildings;2876 – possibility of adequate access for maintenance; and2877

– the ability to safely handle chemical regeneration and chemical sanitation2878 products.2879

3.2 Production of potable water 2880

3.2.1 The quality of the potable water must be monitored in a routine manner. Additional2881tests must be carried out in case there is any change to the raw water source,2882treatment techniques or in the system configuration. If the potable water quality2883changes significantly, the direct use of this water in pharmaceutical processes, or 2884as supplied water for further treatment steps must be reviewed and the results of 2885the review must be documented.2886

3.2.2 In cases where potable water is derived from an internal system for the treatment of 2887raw water, the water treatment steps used and the system configuration must be2888

documented. Changes to the system or its operation must not be carried out until2889they are reviewed and the change is approved by the Quality Assurance2890Department.2891

2892



2942

4 Water purif ication, storage and distr ibution systems2943

4.1 General2944

4.1.1 The storage and distribution system must be configured so as to prevent the recontamination2945

of the water after it is treated and it must undergo a combination of online and offline2946 monitoring so as to guarantee that the appropriate water specification is maintained.2947

4.2 Materials that come in contact with the water systems for pharmaceutical use29484.2.1 Materials that come in contact with water for pharmaceutical use, including piping, valves2949

and setups, seals, diaphragms and instruments must be selected to comply with the2950following objectives:2951

• Compatibility. All materials used must be compatible with the temperature as well as the2952chemical substances used by the system or those in it.2953

• Leakage prevention. All materials that come in contact with the water for pharmaceutical use2954may not have leaks within the working temperature range.2955

• Resistance to corrosion. Purified water and water for injectables are highly corrosive. To2956

avoid failure in the system and contamination of the water the selected materials must be2957 appropriate, the welding process must be carefully controlled and all seals and components2958must be compatible with the piping used. Appropriate plastics with sanitary specifications2959and stainless steel materials are acceptable for pharmaceutical use water systems. When2960stainless steel is used, at least class 316L must be used. The system must undergo2961passivation after the initial installation or after change. When passivation is carried out the2962system must be completely clean before use, and the passivation process must be carried2963out in according to a documented and clearly defined procedure.2964

• Smooth internal finish. Once the water has been purified it is susceptible to microbiological2965contamination and the system is subject to the formation of bio-films when cold storage and2966distribution is applied. Smooth internal surfaces help in preventing roughness and fissures2967within the water system for pharmaceutical use. Frequently the fissures are locations in2968which corrosion may start. The internal finish must have an arithmetical average roughness2969surface of not more than 0.8 micrometers arithmetical average roughness (Ra). When2970stainless steel is used, electropolishing mechanical techniques may be employed.2971Electropolishing improves the stainless steel material resistance to surface corrosion.2972

• Welding. The selected materials for the system must be easily weldable in a controlled2973manner. Control over the process must include at least a qualified operator, records of all2974welds and visual inspection of them.2975

• Flanges or joints design. When flanges or joints are used they must have a hygienic or 2976sanitary design. Checks must be carried out so as to guarantee that the correct seals are2977used and that these are correctly fitted and adjusted.2978

• Documentation. All components in the system must be fully documented and proven through2979the originals or authenticated copies of the material certificates.2980

• Materials. Suitable materials that may be considered as sanitary elements include stainless2981steel 316L (low carbon), polypropylene, polyvinylidene difluoride and perfluoroalkoxy. Other 2982materials, such as non plasticized polyvinyl chloride (uPVC), may be used for less than pure2983water treatment equipment such as ion exchangers and softeners.2984

4.3 System sanitation and microbiological control of the charge2985

4.3.1 The water treatment equipment and the storage and distribution systems used for purified2986water for injectables must be designed so as to prevent microbiological contamination during2987its use, as well as the use of sanitation techniques or sterilization of the system after 2988maintenance or modification intervention. The techniques employed must be considered2989during the system design planning and its performance must be proven during its2990

qualification activities.29912992



29934.3.2 Systems that operate and are kept at high temperatures, in the range of 70 - 80º C, are in2994

general less susceptible to microbiological contamination than systems kept at lower 2995temperatures. When lower temperatures are required due to the water treatment processes2996employed or the temperature requirements for the water to be used, special precautions2997must be taken to prevent the entry and proliferation of microbiological contaminants.2998

4.4 Requirements for storage containers2999

4.4.1 Capacity3000

The storage container capacity must be determined based on the following requirements:3001

• It is necessary to establish the intermediate capacity between the water generation system3002capacity and the consumption at the different points of use.3003

• The water treatment equipment must be able to work continuously for extended periods of time3004to prevent shortfalls and wear to the equipment, which occurs when the equipment is3005equipment is powered on and off frequently.3006

• The capacity must be sufficient to offer a reserve capacity in case the water treatment3007equipment fails or there is an inability to produce water due to sanitation or a regeneration3008cycle. When determining the reserve capacity the supply of sufficient water must be considered3009

to complete a batch being processed, a work period or some other demand logic.3010

4.4.2 Contamination control3011

The following items must be considered for the efficient control of contamination:3012

• The space between the water surface and the reservoir cover is a risk area in which droplets of 3013water and air may come in contact at temperatures that encourage the proliferation of 3014microorganisms. The water distribution system must be configured to guarantee that this space3015in the reservoir is dampened in an efficient manner. A dispersion or distributor system must be3016considered to humidify the surfaces.3017

• Fittings inside the reservoirs must be designed so as to prevent dead zones in which there may3018be microbiological contamination.3019

• Ventilation filters are placed in the reservoirs so as to allow the internal liquid level to fluctuate.3020

The filters must retain bacteria, must be hydrophobic and must be ideally configured so as to3021 allow an integrity test of the location. Offline tests are also acceptable. The use of heated3022ventilation filters must be considered so as to avoid condensation inside the filter matrix, which3023may lead to their blocking and contamination of the reservoirs.3024

• When pressure relief valves and rupture discs are provided to the reservoirs to protect them3025against excessive pressurization, such components must have a sanitary design. The rupture3026disks must be supplied with external rupture indicators so as to prevent the accidental loss of 3027system integrity.3028

4.5 Requirements for water dist ribut ion piping3029

The distribution of purified water for injectables must be carried out using a continuous circulation piping3030cycle. The proliferation of contaminants within the storage tank as well as of the distribution cycle must be3031

controlled.3032Filtration must not be used in distribution cycles or at use points to control biocontamination. Such filters may3033mask the system contamination.3034

4.5.1 Temperature control and heat exchangers3035

4.5.1.1 When heat exchangers are employed to heat or cool the water for pharmaceutical3036use within a system, precautions must be taken so as to prevent the heating or 3037cooling equipment from contaminating the water.3038

4.5.1.2 When the temperature is reduced for process purposes, the reduction must occur 3039in the shortest possible time. The cooling cycles and their duration must be proven3040as satisfactory during the system qualification.3041

3042



30434.5.2 Circulation pumps3044

4.5.2.1 Circulation pumps must have a sanitary design that prevents the system3045contamination.3046

4.5.3 Biocontamination control3047

4.5.3.1 The following techniques may be used either separately or together.3048

• Maintaining continuous circulation with turbulent flow within the water distribution systems3049reduces the propensity of the formation of bio-films. The system must be maintained at a3050specified speed during qualification. During the operation of a distribution system, it is3051unlikely that a short-term fluctuation will cause contamination problems, as long as there is3052no interruption of the flow, flow reversal or loss of pressure.3053

• The system design must ensure the shortest possible length of piping.3054• For systems at room temperature, the piping must be isolated from adjacent hot pipes.3055• Dead points within the piping must not be greater than 1.5 times the size of the diameter of 3056

the stretch in which they are inserted.3057• Pressure calibrators must be separated from the system by means of membranes.3058• Sanitary diaphragm valves must be used.3059• The piping must be laid at an angle so as to allow for drainage.3060

• The growth of microorganisms may be prevented by means of:3061 0 ultraviolet radiation sources in the piping;30620 maintaining the system heated (guideline temperature of 70 - 80º C);30630 periodic sanitation of the system using hot water (guideline temperature of >70ºC);30640 periodic sterilization or sanitation of the system using superheated water or clean3065

vapor; and30660 routine sanitation using ozone or other chemical agents. When chemical sanitation3067

takes place, it is necessary to prove that the agent was removed before using the3068water. Ozone may be effectively removed by using ultraviolet radiation.3069

5 Operational considerations3070

5.1 Qualification3071

All water systems for pharmaceutical use, purified water and water for injectables are considered3072critical quality control systems with direct impact and must be qualified.3073

A three phase approach must be used to satisfy the objective and to prove the reliability and3074robustness of the system in operation for an extended period.3075

Phase 1 A test period of 2 to 4 weeks must be used to monitor the system in an intensive manner.3076During this period the system must operate continuously without failures or deviations in3077performance. The following items must be included in the approach to the tests.3078

• Carry out chemical and microbiological tests in accordance with a defined plan.3079• Daily checks on the supply water quality.3080• Daily sampling of each step in the purification process.3081• Daily sampling at each use point as well as at other defined sampling points.3082• Establishing of appropriate operating ranges.3083• Development and finalizing of operating, cleaning, sanitation and maintenance procedures.3084• Show that production and release comply with the requirements of quality and quantity.3085• Use and adaptation of standard operational procedures (SOPs) for operation, maintenance,3086

sanitation and corrective actions.3087• Check on the warning and action limits.3088• Development and handling procedure in case of test failures.3089

Phase 2 An additional test period of 2 to 4 weeks must be carried out using defined SOPs after the3090satisfactory conclusion of phase 1. The sampling scheme must be the same as in phase 1.3091The water may be used for production purposes during this phase. The evaluation must3092also show:3093

– consistent operation within the established ranges; and3094 – consistent production and supply of water with the required quality and quantities when3095the system is used in accordance with the SOPs.3096

3097



3098Phase 3 Phase 3 must be carried out for one year after the satisfactory conclusion of phase 2. The3099

water maybe used for manufacturing purposes during this phase that has the following3100objectives and characteristics:3101

• To show reliable performance.3102• To guarantee that seasonal variations are evaluated.3103• The locations, sampling frequency and tests may be reduced to the normal routine3104

standards, based on procedures as established during phases 1 and 2.31055.2 Continuous monitoring of the system3106

5.2.1 After the conclusion of phase 3 of the water system qualification program, a review of the3107system must be carried out. After this review a routine monitoring plan must be established3108based on the results from phase 3.3109

5.2.2 Monitoring must include a combination of online monitoring of parameters such as flow,3110pressure, temperature, conductivity and total organic carbon, as well as tests of offline3111samples as to the physical, chemical and microbiological attributes. Offline samples must3112be drawn from use points as well as specific sampling points. Samples from the use points3113must be collected in a similar manner to that adopted when the water is being used.3114

5.2.3 Tests must be carried out as to guarantee compliance with pharmacopeia specifications.3115

5.2.4 An analysis must be carried out on the monitoring data trends.3116

6 Maintenance of water systems3117

6.1 A maintenance program must be established for the water system that considers the following items:3118

– a defined frequency for the system equipment and instruments;3119 – calibration program;3120 – SOPs for specific tasks;3121 – control over the parts to be used;3122 – maintenance schedule and instructions;3123 – record, review and approval of the service carried out; and3124 – record and review of problems and faults during maintenance.3125

7 System reviews3126

The water systems (purified water and water for injectables) must be reviewed at suitable regular 3127intervals. The review team must include representatives from the engineering, quality assurance,3128operations and maintenance sectors. The review must consider such topics as:3129

– changes made since the last review;3130 – system performance;3131 – reliability;3132 – quality control trends;3133 – faults;3134 – investigations;3135

– results that were out of specifications and obtained during monitoring;3136 – changes to the installation;3137 – update to the installation documentation;3138 – record books; and3139 – condition of the current SOPs list.3140

ATTACHMENT V3141

Computerized Systems3142

1 The introduction of a computerized system into the production chain, including storage, distribution and3143quality control does not exempt from the need to attend to other items in the regulations. When3144computerized systems substitute manual operations these cannot impact on the quality of the product.3145

The risk of losing quality control aspects from the previous system by reducing the involvement of 3146operators must be considered.3147

3148



be adopted.3203

3204



320519 In case of computerized system services being contracted there must be a formal contract including3206

the responsibilities of the contracted party.3207

20 When batch release for sale is performed using the computerized system, the system must3208acknowledge that only authorized individual(s) may release the batches and a record of the person in3209charge of this operation is kept.3210

ATTACHMENT VI3211

Good Manufacturing Practices of Herbal Medication3212

This attachment complements the Good Manufacturing Practices for Drug Products, as the need for specific3213management of the control over Herbal Medication.3214

This covers exclusively herbal medication. This does not cover the combination of materials from a3215vegetative source with those from an animal or mineral one, chemical substances, among others.3216

1 General Conditions3217

Due to the inherent complexity of medicinal plants, the production and processing exercise a direct3218influence on the quality of herbal medication. For this reason, the application of Good Manufacturing3219

Practices of Herbal Medication is an essential tool to guarantee the quality of the product.32202 Quality assurance3221

2.1 Besides the adequate use of analytical techniques to characterize herbal medications, the3222quality assurance also requires the control over vegetable-based raw materials besides the3223validated processes and the use of validated analytical methodologies to characterize the3224medication. Therefore, an appropriate Quality Assurance system must be applied in the3225manufacturing of herbal medication.3226

3 Sanitization and Hygiene3227

3.1 Due to its source, vegetation-based materials may contain microbiological contaminants. To3228prevent changes and reduce contamination an increased level of sanitation and hygiene during3229manufacturing is necessary.3230

4 Validation3231

4.1 The company must present a scientific justification to determine the tests to be used during the3232validation of cleaning and process.3233

5 Self-inspection3234

5.1 At least one member of the self-inspection team must have ample knowledge of herbal3235medication.3236

6 Personnel3237

6.1 The release of herbal medication to the market must be authorized by the individual that has3238been trained in the specific processing aspects and quality control of herbal medication.3239

7 Training32407.1 Personnel involved in the manufacturing, control and quality assurance must have suitable3241

training in specific areas of knowledge appropriate to herbal medication.3242

8 Personal Hygiene3243

8.1 The personnel must be protected from contact with potentially allergenic vegetation-based raw3244materials by means of suitable individual protection clothing and equipment.3245

9 Equipment3246

9.1 Cleaning methods with vacuum or liquids are preferable. If cleaning is carried out with liquid the3247equipment must be dried immediately after cleaning so as to prevent the growth of 3248microorganisms. Cleaning with compressed air and brushes must be carried out with care, and,3249if possible, avoided, as these methods increase the risk of contaminating other products.3250

10 Samples Reference Standards3251

10.1 The reference standard for herbal medication may be a sample of the vegetative raw material;3252



or a chemically defined substance, for example, a known active component, a marker substance3253or a known impurity. The reference standard must be of an appropriate quality for its purpose.3254All reference standards must be stored under the appropriate conditions so as to prevent its3255degradation.3256

11 Documentation3257

Specifications3258

11.1 The specifications for vegetable-based raw materials and herbal medication have the objective3259of defining the quality, and to guarantee its safety and efficacy. The specifications must include3260at least the following information:3261

Vegetal raw materials3262

1 The official botanical nomenclature32632 Part of the plant used32643 Tests to identify the main active ingredients or known markers. A sample of the standard must3265

be made available for identification purposes.32664 A description of the plant material based on a visual examination (macroscopic) and/or 3267

microscopic32685 Purity and integrity test results including total ash, and/or insoluble ashes in hydrochloric acid,3269

humidity, research of foreign materials and heavy metals.3270

6 Tests for microbiological contamination, fumigating residues (if applicable), radioactivity (if 3271applicable) and its acceptable limits.3272

7 Other appropriate tests (residual solvents)32738 Qualitative and quantitative analysis on the main active ingredients and/or markers when known.3274

11.2 The vegetable-based raw material derivatives or those containing genetically modified3275organisms must comply with the respective regulations in force.3276

Herbal Medication3277

1 Tests for microbiological contamination and tests for other toxins (when applicable).32782 Uniformity in weight, disintegration period, hardness and friability, viscosity, consistency and3279

dissolution, when applicable.3280

3 Organoleptic characterization.3281 4 Loss through drying.32825 Identity tests, qualitative determination of relevant substances from the plants.32836 Quantification of main active ingredients and/or markers when known.32847 Limit tests for residual solvents.3285

12. Production3286

12.1 If time limits are specified in the main manufacturing instructions, then these limits must not be3287exceeded so as to guarantee the quality of the vegetable-based raw materials and herbal3288medication. The less it is known about the components responsible for the therapeutic activity,3289the stricter this rule must be obeyed.3290

Mixing of batches3291

12.2 The batches may be mixed only if it can be guaranteed that the mixture will be homogenous.3292Such processes must be documented.3293

12.3 The expiry date of the mixed batch must be determined in accordance with the manufacturing3294date of the oldest batch.3295

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