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INTRODUCTION

A good manufacturing practice (GMP) is a production and testing practice that helps to ensure a quality product. Many countries have legislated that pharmaceutical and medical device companies must follow GMP procedures, and have created their own GMP guidelines that correspond with their legislation. Basic concepts of all of these guidelines remain more or less similar to the ultimate goals of safeguarding the health of the patient as well as producing good quality medicine, medical devices or active pharmaceutical products. In the U.S. a drug may be deemed adulterated if it passes all of the specifications tests but is found to be manufactured in a condition which violates current good manufacturing guidelines. Therefore, complying with GMP is a mandatory aspect in pharmaceutical manufacturing.

Although

there are

a

number of them,

all guidelines follow a few basic

principles:

Manufacturing processes are clearly defined and controlled. All critical processes are validated to ensure consistency and compliance with specifications. Manufacturing processes are controlled, and any changes to the process are evaluated. Changes that have an impact on the quality of the drug are validated as necessary. Instructions and procedures are written in clear and unambiguous language. (Good Documentation Practices) Operators are trained to carry out and document procedures. Records are made, manually or by instruments, during manufacture that demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the drug was as expected. Deviations are investigated and documented. Records of manufacture (including distribution) that enable the complete history of a batch to be traced are retained in a comprehensible and accessible form. The distribution of the drugs minimizes any risk to their quality. A system is available for recalling any batch of drug from sale or supply.

Complaints about marketed drugs are examined, the causes of quality defects are investigated, and appropriate measures are taken with respect to the defective drugs and to prevent recurrence.

GMP guidelines are not prescriptive instructions on how to manufacture products. They are a series of general principles that must be observed during manufacturing. When a company is setting up its quality program and manufacturing process, there may be many ways it can full fill GMP requirements. It is the company's responsibility to determine the most effective and efficient quality process.

GMP History

Many of us trained in this history know that the manufacturer, Massengill (now a subsidiary of GlaxoSmithKline), never expressed regret or apologized. As a result, Congress, which is generally reactiveand not proactive, enacted legislation that gave us the current practice of controlling manufacturing. This is not to say that GMPs began with the FD&cAct. FDA, in a recent publication celebrating its centennial, indicated that products, at least food, were regulated during the time of the colonists. 1 For example, in 1641, the Massachusetts Bay Colony required the inspection of pork, beef and fish for adulteration. Also in the 1600s, Virginia had laws that scopped the sale of adulterated wines. In the early 1900s, with the serialization of Upton Sinclair's The jungle and Teddy Roosevelt's investigation of the Chicago slaughterhouses, food processing was in the limelight. This resulted in food GMPs. Drug controls took a latet path. Although Kallet and Schlink, in their classic 100,000,000 Guinea Pigs, written in 1933, recognized the dangers of bad drugs,2 it was not until the Massengill fiasco that Congtess passed the FD&CAct of 1938. This added safety and tolerance requirements in manufacturing where poisonous substances were concerned and authotized factory inspections. This brings us co what is meant by "current" Good Manufacturing Practices. This term refers to the state of the art at a given time. At the time of the Massengill incident, GMP apparently did not include performing quality control checks on raw materials, in-process goods and finished products. So, was the company compliant with industry standards at that time? Difficult as it may be co believe, it probably was. But, as things turned out, cGMP was not enough to ensure safety. Thus, there was a need for formal guidelines and regulations. For the past 70 years, regulated product manufacturing has improved because of controls implemented to ensure safety and efficacy. FDA has promulgated regulations and guidelines

controlling food (21 CFR 1103), dietary supplements (21 CFR 111 4), dtugs (21 CFR 2105 and 211 6), biologics (21 CFR 6007), devices (21 CFR 8208) and tissues (21 CFR 12719). What, then, is the common feature among these regulations? Controlling and checking raw materials, in process goods and finished products is the common thread winding through reviewed and completed documentation. Arbitrarily changing processes and specifications is frowned upon and many changes, even today, require FDA approval. There are, of course, variations in the degree of testing and confirming raw materials. For example, for drugs, the regulations under 21 CFR Part 211 require that all raw materials be tested or that the suppliers meet GMPs established through audit or material testing. Device regulations under 21 CFR 820 do not require the same level of testing of critical components. However, the finished goods manufacturer must verifY or ensure that the critical component does what it is supposed to do. It is not clear why FDA does not require the establishment of specifications and testing for these components. Guidelines for one area of raw material testing involving Quality Control (QC) do not seem clear. Under the Code of Federal Regulations Part 211, as stated above, manufacturers need to control theit raw materials fot production. If the manufacturer tests the "raws" co identifY nonactive ingredients and assays the actives, does it also have to test the raw materials that go into QC reagents? When the question arose several years ago, I contacted CDER twice and never received a response.

THE NEED FOR GOOD MANUFACTURING PRACTICE

People prescribing or being prescribed a medicine has little chance of detecting if it is faulty or not. People who take a medicine trust the doctor who wrote the prescription and the pharmacist who dispensed it. The doctor and pharmacist in turn put their trust in the manufacturer who has a fundamental role in ensuring that the medicine is fit for its purpose and is safe to use. In the case of a blood product the hospital Blood Bank is the “pharmacist” and the NBS is the “manufacturer”. Product testing of medicines and blood products on its own cannot ensure quality. This is because a lot of testing is destructive; meaning only samples from a batch can be tested. Blood products are made in „batches of one‟ (i.e. each blood donation) and it is not possible to test all units for all the things that could have gone wrong. GMP tries to ensure that quality is built into the organisation and the processes involved in manufacturing. The activities involved in achieving quality cover much more that the manufacturing

operations themselves. There must be clear written specifications for the materials, the packaging and the products themselves. There must be clear written instructions and procedures covering processing and testing, handling, storage, receipt and dispatch. Suitable premises, equipment and trained staff must be specified and made available.

Guideline versions

GMPs are enforced in the United States by the US FDA, under Section 501(B) of the 1938 Food,Drug,and Cosmatic Act (21 USCS § 351). The regulations use the phrase "current good manufacturing practices" (cGMP) to describe these guidelines. Courts may theoretically hold that a drug product is adulterated even if there is no specific regulatory requirement that was violated as long as the process was not performed according to industry standards. [citation needed] As of June 2010, a different set of cGMP requirements apply to all manufacturers of dietary supplements. [1]

The World Health Organisation (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry pharmaceutical in over one hundred countries worldwide, primarily in the developing world. The Europeon union GMP (EU-GMP) enforces similar requirements to WHO GMP, as does the Food and Drug Administration's version in the US. Similar GMPs are used in other countries, with Australia,Canada,Japan,Singapore and others having highly developed/sophisticated GMP requirements. In the United kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as "The Orange Guide", which is named so because of the color of its cover; it is officially known as Rules and Guidance for Pharmaceutical Manufacturers and Distributors. [2]

Since the 1999 publication of GMPs for Active Pharmaceutical Ingredients, by the International Conference on Harmonization International Conference (ICH), GMPs now apply in those countries and trade groupings that are signatories to ICH (the EU, Japan and the U.S.), and applies in other countries (e.g., Australia, Canada, Singapore) which adopt ICH guidelines for the manufacture and testing of active raw materials.

Enforcement

Within the European Union, GMP inspections are performed by National Regulatory Agencies (e.g., GMP inspections are performed in the United

Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA)); in the Republic of Korea (South Korea) by theKorea Food&Drug Administration (KFDA); in Australia by the Therapeutical Goods Administration (TGA); in South Africa by the Medicines Control Council (MCC); in Brazil by the Agencia Nacional de Vigilancia (National Health Surveillance Agency Brazil) (ANVISA); in Iran, in India gmp inspections are carried out by state FDA and these FDA report to Central Drugs Standard Control Organization [3] and Pakistan by the Ministry of Health; [4] , Nigeria has NAFDAC and by similar national organisations worldwide. Each of the inspectorates carry out routine GMP inspections to ensure that drug products are produced safely and correctly; additionally, many countries perform pre- approval inspections (PAI) for GMP compliance prior to the approval of a new drug for marketing.

Regulatory agencies (including the FDA in the U.S. and regulatory agencies in many European nations) are authorized to conduct unannounced inspections, though some are scheduled. FDA routine domestic inspections are usually unannounced, but must be conducted according to 704(A) of the FD&C Act (21 USCS § 374), which requires that they are performed at a "reasonable time". Courts have held that any time the firm is open for business is a reasonable time for an inspection.

GMPs Today

The last items I wish to discuss are some actions FDA has taken to "improve" GMPs and, thereby, product quality. Legislation and regulations requiring controls for manufacturing give rise to uniformity of product within certain limits of variation. FDA published Quality Systems Approach toPharmaceutical CGMP Regulations in September 2006. 15 It is similar to the Quality Systems Regulation fot devices and emphasizes quality by design in product development and risk management. According to the guidance, "Quality by design means designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process." Maybe I misunderstand this FDA initiative, but isn't this what manufacturers do already? One item, "Quality Risk Management," is an outgrowth of the ICH guidance on risk (Q9) and is new in this FDA guidance. Starting risk management early in the development process increases quality by reducing error.

Other good practices

Other good-practice systems, along the same lines as GMP, exist:

Good laboratory Practice (GLP), for laboratories conducting non- clinicalstudies (toxicology and pharmacology studies in animals);

Good clinical practice (GCP), for hospitals and clinicians conducting clinical studies on new drugs in humans;

Good regulatory practice (GRP), for the management of regulatory commitments, procedures and documentation.

Good Distribution Practice (GDP) deals with the guidelines for the proper distribution of medicinal products for human use

Good Transportation Practice (GTP) deals with the guidelines for the proper domestic and international transportation of medicinal products for human use

Collectively, these and other good-practice requirements are referred to as "GxP" requirements, all of which follow similar philosophies. (Other examples include good agriculture practices, good guidance practices, and good tissue practices.) In the U.S., medical device manufacturers must follow what are called "quality system regulations" which are deliberately harmonized with ISO requirements, not cGMPs

Good Laboratory Practice

GLP is a quality system concerned with the organisational processing process and conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. [3]

GLP and the USFDA

The United States FDA has rules for GLP in 21CFR58. Preclinical trials on animals in the United States of America use these rules prior to clinical research in humans.

Research in the US not conducted under these restrictions or research done outside US not conducted according to the OECD Guidelines (or FDA rules) might be inadmissible in support of a New Drug Application in the US.

Good Clinical Practice

Good Clinical Practice (GCP) is an international quality standard that is provided by International Conference on Harmonisation (ICH), an international body that defines standards, which governments can transpose into regulations for clinical trials involving human subjects.

Good Clinical Practice guidelines include protection of human rights as a subject in clinical trial. It also provides assurance of the safety and efficacy of the newly developed compounds.

Good Clinical Practice Guidelines include standards on how clinical trials should be conducted, define the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors. In the pharmaceutical industry monitors are often called Clinical Research Associates.

Good Clinical Practice

Good Clinical Practice (GCP) is an international quality standard that is provided by International Conference on Harmonisation (ICH), an international body that defines standards, which governments can transpose into regulations for clinical trials involving human subjects.

Good Clinical Practice guidelines include protection of human rights as a subject in clinical trial. It also provides assurance of the safety and efficacy of the newly developed compounds.

Good distribution practice

Good Distribution Practice (GDP) deals with the guidelines for the proper distribution of medicinal products for human use. GDP is a quality warranty system, which includes requirements for purchase, receiving, storage and export of drugs intended for human consumption.

GDP regulates the division and movement of pharmaceutical products from the premises of the manufacturer of medicinal products, or another central point, to the end user thereof, or to an intermediate point by means of various transport methods, via various storage and/or health establishments.

GMP REQUIREMENTS

The current version of “Rules and Guidance for Pharmaceutical Manufacturers and

Distributors” has nine chapters, which have the following titles:

  • 1. Quality Management

  • 2. Personnel

  • 3. Premises and Equipment

  • 4. Documentation

  • 5. Production

  • 6. Quality Control

  • 7. Contract Manufacture and Analysis

  • 8. Complaints and Product Recall

  • 9. Self Inspection

There are also a number of Annexes, some of which are relevant to our

activities, such as those dealing with computer systems validation and irradiation.

Quality Management

The manufacturer must produce products that are fit for their intended use and do not place patients at risk. Senior management is responsible for product quality and safety but the participation and commitment of staff is vital, as is the support of suppliers. There must be a comprehensive and effectively implemented Quality Assurance system, incorporating Good Manufacturing Practice and Quality Control. The system should be fully documented and its effectiveness monitored. All parts of the Quality Assurance system should be adequately resourced with competent personnel and proper premises, equipment and facilities.

Personnel

A satisfactory system of Quality Assurance depends on people.

There must be sufficient qualified personnel to carry out the necessary tasks. The responsibilities of individuals should be clearly understood and recorded. All personnel should be aware of the principles of GMP. All personnel should receive initial and continuing training, relevant to their needs.

Premises and Equipment

Premises and equipment must be built and maintained to suit the operations being carried out. The layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance. Premises and manufacturing equipment should be cleaned according to detailed written procedures. The entry of unauthorised people should be prevented and production and

storage areas should not be used as a „right of way‟.

Measuring, weighing, recording and control equipment should be calibrated regularly. Defective equipment should be removed if possible or labelled as defective if not.

Documentation

Clearly written documentation prevents

errors

from spoken

communication. Specifications, instructions, procedures and records must be free from errors and available in writing. Documents should be unambiguous, have clear and concise contents, a title and purpose. Documents should be regularly reviewed and kept up to date.

Documents should not be hand-written (except for the entry of data).

Records should be completed in ink.

Any alteration to a record should be signed and dated with the original entry still visible.

Production

Production activities must follow clearly defined procedures and should be performed only by trained and competent people. All materials and products should be stored under the appropriate conditions and in an orderly fashion to permit batch segregation and stock rotation. At each stage of processing, products and materials should be protected from microbial and other contamination. Any deviation from instructions or procedures should be avoided. How ever changes may be approved in writing by a competent person, with the involvement of the Quality Department if possible. Significant amendments to the manufacturing process, including any change in equipment or materials which may affect product quality and/or reproducibility of the process should be validated. Validation studies should be conducted to demonstrate that the process, equipment and/or activity actually leads to the expected results.

Quality Control

Quality Control is not confined to laboratory operations, but must be

involved in all decisions that may concern the quality of the product. The independence of Quality Control from Production is considered

fundamental to the satisfactory operation of Quality Control. Sampling of product should take place in accordance with written procedures.

Analytical methods should be

.

Quality control specifications and tests

Thin-layer chromatography screening tests for antimalarials

The Committee noted and accepted the recommendations made during a consultation held in Geneva in September 2001 on thin-layer chromatography (TLC) screening tests for antimalarials while also noting that further experimental work was necessary.

Radiopharmaceuticals

The Committee was informed that The International Pharmacopoeia. contained only general methods for the analysis of radiopharmaceuticals; there were no individual monographs for such products, mainly because they were not on the WHO Model List of Essential Drugs.

Pharmacopoeial monographs on antiretrovirals

The Committee adopted the recommendations on the development of pharmacopoeial monographs on antiretrovirals made during a consultation held in Geneva in September 2001, but advocated that the Secretariat should review the list of substances and products in accordance with the new treatment pattern

regimen. For a number of antiretrovirals, manufacturers‟ specifications are available. The Committee therefore recommended that WHO should seek information from additional manufacturers willing to collaborate. It was suggested that national authorities with experience in evaluating and testing new antiretrovirals should be asked for their support. This also applies to the possibility of obtaining samples.

Thin-layer chromatography screening tests for antituberculosis drugs

The Committee noted and accepted the recommendations on TLC screening tests for antituberculosis drugs made during a consultation held in Geneva, in

September 2001. The document prepared during this consultation is ready for circulation to WHO collaborating centres for validation.

Draft monograph on rifampicin, isoniazid, pyrazinamide and ethambutol

hydrochloride tablets The Committee noted the collaboration between WHO and The United States Pharmacopeia in developing this monograph, received the monograph as a working document and approved the recommendations made during a WHO consultation held in Geneva in September 200

Quality control international reference materials The reports of the WHO Collaborating Centre for Chemical Reference Substances for 1999 and 2000 were presented to the Committee. The Committee noted that the prices of reference substances had not changed for the past 4 years, and that there would be a small increase in price in the near future. It was also noted that only substances that were related to the WHO Model List of Essential Drugs were supplied as reference substances. The Committee adopted the reports and expressed its appreciation to the WHO Collaborating Centre for Chemical Reference Substances for its work.

Quality

assurance

good

manufacturing

Practices Specific GMP

guidelines for radiopharmaceutical products

The Committee was informed of the collaboration between WHO and the IAEA in developing these specific GMP guidelines. The Committee was also informed that these guidelines are supplementary to the general requirements for GMP set out in WHO‟s GMP for pharmaceutical products (Annex 4). The Committee adopted the guidelines, noting that several minor editorial changes were required (“Guidelines on Good Manufacturing Practices for radiopharmaceutical).

GMP guidelines for active pharmaceutical ingredients

The Committee was informed of the background to the development of the ICH GMP guidelines for active pharmaceutical ingredients (APIs), including the earlier involvement of the Pharmaceutical Inspection Cooperation Scheme in initiating the preparation of this guide. The Committee recognized the difficulty that countries would have in implementing the ICH GMP guide in a short period of time. The Committee was informed that, from a legal standpoint, WHO cannot simply take over any GMP document from another source. The Committee therefore considered that it would be best for the current WHO GMP for APIs to be revised to reflect

current GMP requirements. products”) (Annex 3).

WHO GMP: main principles for pharmaceutical products

The Committee was informed of the main changes that had been made in

revising these GMP guidelines, to incorporate texts and recommendations published separately, and to bring the guidelines into line with current GMP

requirements, particularly in relation to validation, authorized persons, documentation and definitions.

WHO basic training modules on GMP

WHO has developed GMP training modules to promote GMP implementation in response to difficulties in achieving GMP compliance in developing countries. The modules are available on CD-ROM and via the WHO web site. The CD-ROMs have been distributed free of charge to all Member States and other relevant organizations. The Committee had the opportunity to view the contents of the training modules.

Complaints and Product Recall

All complaints and other information concerning potentially defective products must be reviewed carefully according to written procedures. The person responsible for Quality Control should normally be involved in the study of product defects. There should be written recall procedures that are regularly checked and updated where necessary. Recall operations should be capable of being initiated promptly and at any time.

Self Inspection (Internal Audit)

Internal

Audits

should

be

conducted

in

order

to

monitor the

implementation and compliance with GMP. Internal Audits should be conducted in an independent and detailed way by designated competent persons.

NBS Scientific and Technical Training.

 

PRACTICAL CONSIDERATIONS

In addition to the key aspects of the requirements that GMP imposes on us (listedabove), there are some practical aspects of GMP, which affect all staff working in relevant areas.

Documentation

Most people dislike paperwork. Computers are taking over some of the work but we still have lots of paper in use, which although a „nuisance‟, helps to keep our products safe. Documentation is needed to allow us to:

Check that we have done what we should have done.

Keep records of information, results and actions taken.

Investigate problems.

There are a number of different types of document in use. Manufacturing and

other instructions are contained within Standard Operating Procedures (SOPs), which describe specific tasks in a stepwise fashion, instructing staff what to do and if necessary how to do it, although the how is mainly part of training and job skills.

Although often called „operating‟ procedures, there are other SOPs which deal

with more general aspects of procedure such as validation, corrective action, quality incidents, training and so on which are mostly used by managers and supervisors. Specifications for products and how they are to be tested are contained in documents such as the „Guidelines for the Blood Transfusion Service‟ (i.e. the “Red Book”). We use these specifications when we are developing our manufacturing methods and particularly when drawing up our quality standards and test methods.

Labelling

We use labels for internal identification purposes and also to inform users about our products and about the contents of the container to which the label is attached. Labels are of vital importance. An incorrect label could lead to a disaster. Therearesome rules regarding the use of labels:

They should always be held securely and not left lying around.

Always notify somebody if labels are seen to be coming detached appear

to be incorrect or are in the wrong place. Report any labels that are damaged or dirty.

Never remove a label which has been incorrectly applied and never stick a new label over an old one of the same type, although planned ““over- sticking”” e.g.putting a blood group label onto a base label is allowed.

Cleanliness

One of the requirements of GMP is to prevent contamination of products. Dust, particles and dirt can contaminate products as can chemicals and micro- organisms. Dirt harbours micro-organisms and that is why our workplaces must be really clean, not just look clean. The air is one source of contamination as are insects such as flies. People are also a source, which is why there are hygiene rules that must be followed. Key aspects of these rules are to maintain a standard of personal hygiene, wear protective clothing as directed, never eat drink or smoke in work areas, keep your work areas clean and tidy and be on the alert for possible sources of contamination.

Training

GMP ultimately depends on people. The individual skills and understanding people about their work can be developed by training. It is also important for product safety that staff do not carry out tasks for which they have not been

trained and which either they or their supervisors think they are not competent to carry out.Training should be given on both the theory and practice of the work being undertaken in a particular area, as well as relevant „on -the-job‟ (i.e. task-based) training. Records of this training must be available.

Basic Rules of GMP

Here is a list of the basic rules, required by GMP:

  • 1. Make sure you have the correct written instructions before starting a task.

  • 2. Do not carry out a task for which you have not been trained or in which you

do not feel competent.

  • 3. Always follow instructions precisely. Do not cut corners. If in doubt, ask.

  • 4. Check that the equipment and the materials that you are using are the correct

ones, as stated in the procedure.

6.

Always be on your guard for labelling errors.

  • 7. Keep everything clean and tidy (including yourself!).

  • 8. Always be on the look out for mistakes, defects and unusual events. Report

them immediately.

  • 9. Make clear accurate records of what was done and the checks carried out.

Ultimately quality depends on people. Although processes get more automated there are still many activities which require the constant care and attention of staff.

Links to Worldwide GMP Codes and Regulations

Links to Worldwide GMP Codes and Regulations Below are links to the main international and nationalWHO GMPs for Active Pharmaceutical Ingredients (APIs) WHO GMPs for Finished Pharmaceutical Products WHO GMPs for Herbal Products ICH GMPs for Active Pharmaceutical Ingredients IPEC GMPs for Pharmaceutical Excipients (available for purchase from this link to IPEC)     Australia (TGA) Code of GMPsCanada (HPFBI) GMP GuidelinesEurope (EU) GMPsJapan (MHW) GMPs (available for purchase in English from this link to Yakuji Nippo publishers)  United States (FDA) - cGMPs for Finished Pharmaceutical Products Contents of the GMP MANUAL GMP in Practice 1. Pharmaceutical Quality System (PQS) 2. Personnel 3. Premises 4. Facilities and Equipment 5. Pharmaceutical Water 6. Qualification 7. Process Validation 8. Cleaning Validation 9. Computer System Validation 10. Considerations on Risk Management 11. Production 12. Sterile Production 13. Packaging 14. Laboratory Controls 15. Documentation 16. Research and Development " id="pdf-obj-16-4" src="pdf-obj-16-4.jpg">

Below are links to the main international and national GMP Codes (Directives, Regulations) worldwide:

Contents of the GMP MANUAL

GMP in Practice

  • 1. Pharmaceutical Quality System (PQS)

  • 2. Personnel

  • 3. Premises

  • 4. Facilities and Equipment

  • 5. Pharmaceutical Water

  • 6. Qualification

  • 7. Process Validation

  • 8. Cleaning Validation

  • 9. Computer System Validation

    • 10. Considerations on Risk Management

    • 11. Production

    • 12. Sterile Production

    • 13. Packaging

    • 14. Laboratory Controls

    • 15. Documentation

17.

Contractors and Suppliers

  • 18. Inspections

  • 19. Quality Unit

  • 20. Continual Improvement

  • 21. Active and Inactive Ingredients

  • 22. Biologics

  • 23. Medical Devices

GMP Regulations

  • A. Empty Register

  • B. Empty Register

  • C. EU Directives and Guidelines

  • D. USA: CFR and FDA Guidelines

  • E. ICH-Guidelines

  • F. PIC/S Guidelines

  • G. GMP of other Regions (this

chapter is supplied on CD-ROM and online only)

  • - WHO Guidelines

  • - Health Canada - GMP Guidelines

  • - Japanese Regulations

    • H. Information