Chapter 2.4 current good manufacturing practice

BNN20303Quality Assurance and Quality Control in Biotechnology

By: Dr. Nadirul Hasraf Mat Nayan

CHAPTER 2QUALITY MANAGEMENT,

CONTROL AND ASSURANCE

Chapter OverviewCHAPTER 2: QUALITY MANAGEMENT,

CONTROL AND ASSURANCECHAPTER 2.1: Introduction to Quality Management,

Control and Assurance

CHAPTER 2.2: The difference between Quality Control and Quality Assurance

CHAPTER 2.3: Quality Control and Quality Assurance in Biotechnology

CHAPTER 2.4: Current Good Manufacturing Practice (cGMP)

Chapter 2.4

Current Good Manufacturing Practice

(cGMP)

Chapter OverviewCHAPTER 2.4: CURRENT GOOD MANUFACTURING

PRACTICE (cGMP)

CHAPTER 2.4.1: Introduction to cGMP

CHAPTER 2.4.2: Purpose of cGMP

CHAPTER 2.4.3: Elements of cGMP Compliant

CHAPTER 2.4.4: Key Aspects of cGMP compliance

CHAPTER 2.4.5: Characteristics of an Exceptional cGMP

Chapter Overview

CHAPTER 2.4: CURRENT GOOD MANUFACTURING PRACTICE (cGMP)

CHAPTER 2.4.6: Benefits of cGMP

CHAPTER 2.4.7: Consequences if cGMP’s Are Not Followed

CHAPTER 2.4.8: cGMP Case Study

CHAPTER 2.4.9: Conclusions

Chapter 2.4.1

Introduction to cGMP

2.4.1: Introduction to cGMP What is cGMP?

cGMP refers to the Current Good Manufacturing Practice regulations enforced by the United States Food and Drug Administration (FDA).

cGMP provide systems that assure proper design, monitoring, and control of manufacturing processes and facilities.

Adherence to the cGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations.

2.4.1: Introduction to cGMP What is cGMP?

This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories.

This formal system of controls at a pharmaceutical company, if adequately put into practice, helps to prevent instances of contamination, mix-ups, deviations, failures, and errors.

This assures that drug products meet their quality standards.

2.4.1: Introduction to cGMP

2.4.1: Introduction to cGMP

2.4.1: Introduction to cGMP Who Interprets and Enforces cGMP Law?

The FDA (Food and Drug Administration) is an agency which is responsible in interpreting and enforcing the cGMP law.

The FDA is an agency within the Department of Health and Human Services and consists of eight centers.

2.4.1: Introduction to cGMP Who Interprets and Enforces cGMP Law?

The eight centers under FDA:

Chapter 2.4.2

Purpose of cGMP

2.4.2: Purpose of cGMP

i. Provides a high level assurance that medicines are manufactured in a way that ensures their safety, efficacy (effectiveness) and quality.

ii. Medicines are manufactured to comply with their marketing authorization.

The purpose of implementing cGMP in a business are enumerated as under:

2.4.2: Purpose of cGMP

iii. Quality is built in through testing, which is part of cGMP and provide a good level of quality assurance.

iv. cGMP help boost manufacturer export opportunities, due to the facts that, most countries will accept the import and sale of medicines only if they have been manufactured according to internationally recognized cGMP.

The purpose of implementing cGMP in a business are enumerated as under:

2.4.2: Purpose of cGMP The purpose of implementing cGMP in a business:

cGMP offer a “trust chain”

Chapter 2.4.3

Elements of cGMP Compliant

2.4.3: Elements of cGMP Compliant Below are the elements of cGMP that manufacturers worldwide

must adhere to in order to produce a quality drugs, which comply to the cGMP:

1. Organization and Personnel2. Quality Unit3. Building and Facilities4. Equipment5. Component/ Materials Control6. Production/ Process Control7. Packaging and Labeling Control8. Holding and Distribution9. Laboratory Controls10. Quality Records

1. Organization and Personnel

Management Responsibility

Responsible to facility, quality system, organization structure and ensuring adequate resources.

Responsible for actions of those reporting to them.

Responsible for reviewing products annually, and procedures routinely.

Responsible for providing adequate resources to perform operations

2.4.3: Elements of cGMP Compliant

1. Organization and Personnel

Personnel Responsibility Any person shown at any time to have an apparent

illness that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials or medicines until the condition is no longer judged to be a risk.

All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment or personnel) that they consider may adversely affect the products.


2. Quality Unit

Responsible for approval of rejection of:

All components, raw materials, containers, closures, subassemblies, packaging, labeled finished products, process validation reports, procedures and product specifications.

Investigate reports for non-conformances and out-of-specifications (OOS’s).


2. Quality Unit

Responsible for reviewing production records and ensuring that no errors have occurred.

Responsible for releasing product for use.

Must be independent of manufacturing.

QC laboratories should be separated from production areas. Areas where biological, microbiological or radioisotope test methods are employed should be separated from each other.


3. Building and Facilities

Building must be designed with adequate size and space for operation in order to helps eliminate mix-ups.

Facilities must be validated. Validation will help to avoid the most common problem of them all, spending time and money building non-conformances facilities.

Utilities such as water systems or electrical must be validated. This is to ensure that that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).


3. Building and Facilities

Facilities should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.

The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.


4. Equipment

Equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out.

The layout and design of equipment must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products.


4. Equipment

Laboratory equipment and instruments should be suited to the testing procedures undertaken.

Washing, cleaning and drying equipment should be chosen and used so as not to be a source of contamination.

Production equipment should not present any hazard to the products.

The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to an extent that would affect the quality of the product.


5. Component/ Materials Control

Suppliers must be evaluated and approved and monitored for quality.

Incoming materials must be tested before they can be accepted for use.

Materials must be placed in stores or issued according to FIFO stock rotation.

Materials must be stored so that they are not mixed up, damaged, or contaminated.


5. Component/ Materials Control


First-In, First-Out (FIFO) is a method that assumes that inventory purchased or manufactured first is sold first and newer inventory remains unsold.

6. Production/ Process Control

Have and follow procedures- A good procedure is written step-by-step procedure that provides a road map for controlled and consistent performance.

Any deviations from the procedures must be recorded and justified.


7. Packaging and Labeling Control

Label is a display of a written, printed or graphic matter upon the immediate container of any article.

Labeling is the label and any other packaging materials or container that is printed.

Procedures must exist that document receiving, identify, storage, handling, sampling and testing of labels and ensure that integrity is maintained throughout production and use of product.


7. Packaging and Labeling Control

Labeling must be separated physically in storage to avoid mix-ups.

Wording of labels cannot be changed unless the FDA is notified.

Labeling must be inspected prior to issuing to production.

All labels must be reconcile (accounted for) if not 100% inspected.


8. Holding and Distribution

Warehousing procedure should address:

Distribution procedures should address:


Quarantine of drug products.

Storage of products under appropriate conditions.

FEFO (First Expiring First Out).

Traceability of products lots or batches.

9. Laboratory Controls


Written procedures must be established and followed.

All actions must be documented at the time of performance.

Calculations need to be recorded.

Second person must reviews records.

Data must be directly recorded into appropriate records.

An Out-of-Specification (OOS) result must be investigated and root cause identified.

Laboratory data is considered to be a quality record.

10. Quality Records

Quality records are the proof that the procedures were followed and they show traceability of products.

The quality records must contains the following:


1) Lot History Records2) Laboratory Notebooks3) Protocols4) Reports5) Logbooks6) Distribution Records7) Complaint Files

10. Quality Records

Records are legal documents and can be subpoenaed in a court of law as evidence.

Signatures on documentation have the same meaning as on any kind of contract.

Information must be recorded and signed for at the time of performance on the original record.


Chapter 2.4.4

Key Aspects of cGMP compliance

2.4.4: Key Aspects of cGMP compliance

There are many important parts of cGMP compliance. Of these, the most critical are:

i. Proper Documentation and Records

If it is not recorded it never happened according to the inspectors.

It is important that all actions, events and decisions relating to the quality of the product must be recorded at the appropriate level of detail in a controlled way.



ii. Control of Materials

This refers to ensuring that all materials used, whether they be the raw materials, components such as bottles or stoppers, and packaging materials, are of the sufficient quality and are traceable.



iii. Thorough Housekeeping and Cleaning

cGMP requires that people work in an orderly and methodical way and that work areas are neat, tidy and there is segregation between tasks where required.

This will reduce the potential for errors and mix-ups to occur.



iv. Responsible Personnel Behaviour

This includes such areas as reporting incidents and errors immediately or behaving appropriately in controlled areas.



v. Process Control At All Steps

This level of control relates to ensuring that all parameters are in control throughout the manufacturing process (e.g. time, temperature, pH) and reporting immediately if there is a noticeable drift or adverse trend.



vi. Maintenance of Equipment

This involves ensuring all equipment used in the manufacture of product is 'fit for purpose' and is cleaned, maintained, calibrated and verified as appropriate and labelled or recorded as such.

This is supported through initial and on-going validation.

Any equipment not fit for purpose should ideally be removed or clearly labelled.

Chapter 2.4.5

Characteristics of an Exceptional cGMP

2.4.5: Characteristics of an Exceptional cGMP

Business with exceptional cGMP have the following characteristics:



1. Involvement of the managementThe senior management is responsible to attain the

company’s quality objectives.

All different departments and all levels within departments should be involved, and it’s the senior management who should facilitate this.

Also suppliers and distributors should be involved.



1. Involvement of the managementThe senior management should make available the

required resources.

The basic of the quality system is the quality statement and quality policy, by the senior management.



2. Annual Product Quality ReviewReview of starting materials and packaging materials,

especially from new sources.

Review of in-process control results and finished product analytical control results.

Reviews of out-of-spec situations, deviations and changes from specifications.


2. Annual Product Quality Review

Objectives of Product Quality Review:

I. To review and verify the consistency and appropriateness of the existing process.

II. To identify and highlight any trends in the process.

III. To identify any possible product or process improvements.



3. Quality risk management

Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the drug product across the product lifecycle.

Quality risk management activities are usually undertaken by interdisciplinary teams.



3. Quality risk managementWhen teams are formed, they should include experts

from the appropriate areas (e.g., quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics, and clinical), in addition to individuals who are knowledgeable about the quality risk management process.



4. Complaints handling All complaints and other information concerning potentially

defective products must be carefully reviewed according to written procedures and corrective action should be taken.

All decisions and measures taken should be recorded.

Inform competent authorities in case of serious quality problems such as faulty manufacture, product deterioration or counterfeiting.



5. Self-Inspection Purpose of self-inspection is to evaluate whether a

company’s operations remain compliant with cGMP.

The self-inspection programme should cover all aspects of production and quality control.

The programme should also be designed to detect shortcomings in the implementation of cGMP and recommend corrective actions



5. Self-Inspection The self-inspection programme should be performed

routinely and also on special occasions such as recalls or repeated rejections.

Frequency of the programme should normally be at least once a year and may depend on company requirements, as well as activities.



5. Self-Inspection Performed by team appointed by management, with

authority, sufficient experience, expertise in their own field, have knowledge of cGMP and may be from inside or outside the company.

Chapter 2.4.6

Benefits of cGMP

2.4.6: Benefits of cGMP What are the benefits of cGMP?

cGMP outline a quality system that reduces or prevents errors.

cGMP ensures products are safe for use in humans.

cGMP prevent and control contamination and cross-contamination.

cGMP minimizes variations in potency of the drug.

2.4.6: Benefits of cGMP What are the benefits of cGMP?

cGMP ensures reproducible physiological activity.

cGMP prevent side effects and toxicity due to variations in drug content and potency.

cGMP prevents mislabeling and adulteration.

Chapter 2.4.7

Consequences if cGMP’s Are Not Followed

2.4.7: Consequences if cGMP’s Are Not Followed

i. Adulteration:

ii. Legal consequences:

A company produced drugs will be deemed to be adulterated if the methods used for its manufacture, processing, packing, and holding do not conform with cGMP.

2.4.7: Consequences if cGMP’s Are Not Followed

iii. Business consequences:

Chapter 2.4.8

cGMP Case Study

2.4.8: cGMP Case Study

GROUP PRESENTATION

Case #1: IV Bottle Contamination (Abbott Laboratories)

Case #2: Hemodialysis Filters (Baxter Pharmaceuticals)

Case #3: Albuterol Inhalers (Schering Plough)

2.4.8: cGMP Case Study

GROUP PRESENTATION

Case Study GroupCase #1 1, 4, 7, 10Case #2 2, 5, 8Case #3 3, 6, 9

* Presentation must be more than 15 slides* Each group members must present

Chapter 2.4.9

Conclusions

2.4.9: Conclusions

Making poor-quality products does not save money.

In the long run, it is more expensive finding mistakes after they have been made than preventing them in the first place.

cGMP are designed to ensure that mistakes do not occur.

2.4.9: Conclusions

Implementation of cGMP is an investment in good-quality medicines, and will improve the health of both the individual patient and the community, as well as benefiting the pharmaceutical industry and health professionals.

Making and distributing poor-quality medicines leads to loss of credibility for everyone, including public and private health care services and pharmaceutical manufacturers.

Documents

Chapter 2.4 current good manufacturing practice