Week 3 - Good Manufacturing Practice

Question 1

How many GMP principles are there and what are they (briefly)?

Answer 1

9 key principles:

1. Quality Management (Quality Assurance)
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 *

Question 2

What is GMP with reference to pharmaceutical production, what is the main objective?

Answer 2

• GMP is a constituent of quality assurance, which ensures that pharmaceutical products are constantly produced and regulated to the quality standards issued by marketing authorities.
• The main objective of GMP is to minimise risks associated with the manufacturing of pharmaceutical products.

Question 3

What are the types of risk with regards GMP?

Answer 3

• risks can be categorised into two main types: cross-contamination and generic errors.

Question 4

What must happen to be in accordance with GMP regarding definition of manufacturing procedures and criterion and validation?

Answer 4

• All manufacturing procedures should be well-defined: should comply with the relevant specifications and be able to consistently manufacture pharmaceutical products to a high standard of quality.
• Criterion and validation should be performed.

Question 5

What must happen to be in accordance with GMP regarding resources and instruction?

Answer 5

• All required resources must be available: including qualified personnel, suitable premises, storage, adequate equipment, materials and services; authorised procedures.
• All instructions and procedures should be clearly written.

Question 6

What must happen to be in accordance with GMP regarding records and the handling of complaints?

Answer 6

• Adequate records should be made of all stages in the manufacturing process and distribution stage: which will enable others to verify if the product has been made to meet the quality standards and also to provide a complete history of events for traceability purposes.
• Satisfactory measures should be taken to address all complaints and to prevent the recurrence of manufacturing defective products.

Question 7

In GMP what are staff responsible for and how can we assure that this happens?

Answer 7

• Responsible for the establishment and the upkeep in a satisfactory system of quality assurance and the proper manufacture of medicinal products.
• Qualified personnel are required to perform all the duties, which are the responsibility of the manufacture.
• To be effective, all personnel should be fully aware of their responsibilities, undergoes sufficient training, and understand the principles of GMP.

Question 8

In regards to medicinal products what is a qualified person (QP), what is their legal duty and what are their responabilities?

Answer 8

• QP is paramount to the safe control of medicines and must have extensive training and understanding of all aspects associated with manufacturing and distribution.
• Main legal duty of the QP is to certify batches of medicinal products before they are released on the market or used in a clinical trial.
• Responsible for undertaking their responsibilities in accordance with a professional Code of Practice.

Question 9

What must a manufacturer have to record duties and what do Key Personnel include?

Answer 9

• The manufacturer should have an organisation chart and the allocated duties should be recorded.
• Key Personnel of the operation include the head of Production and the head of Quality Control, which must be independent from each other.

Question 10

What are the duties of the head of the Production department?

Answer 10

Ensure:

• Products are manufactured and stored in accordance to the relevant documentation, to preserve the quality of the product;
• Strict implementation of production operations and to approve relating instructions;
• Authorised person(s) evaluate and sign the production; records prior to sending it to the Quality Control Department
• Suitable validations are performed;
• Personnel in his/her department undergo sufficient training.

Question 11

What are the duties of the Head of Quality Control Department?

Answer 11

• Approve/ reject starting materials, packaging materials, intermediate bulk and the completed manufactured product
• Assess batch records
• Assess maintenance of the department, premises and equipment
• Ensure that relevant validations are performed

Question 12

What are some of the duties shared by the Head of Production and the Head of Quality Control?

Answer 12

• Certification of writing procedures and other relevant documentations
• Assessing and regulating the manufacturing area
• Process validation
• Training
• Certifying and regulating suppliers of materials and contract manufacturers
• Monitoring compliance with GMP requirements and principles

Question 13

In accordance with GMP standards, what are manufacturers required to qualify?

Give some examples

Answer 13

• Pharmaceutical company is recommended to identify what qualification and validation work is needed to verify that the critical aspects of the operational processes are regulated.
• E.g. any aspect of operation including significant alterations to the equiptment, premises or processes, which may alter the quality of the pharmaceutical product, should be qualified and validated.

Question 14

What should the qualification and validation give proof of?

Answer 14

Should provide documentary proof that:

• Equipment, utilities, premises and processes have been designed in accordance with the GMP standards.
• Equipment, utilities and premises have been built and installed to comply with the design specifications.
• Operational process will consistently produce a product matching its predetermined specifications and quality attributes.

Question 15

Outline the personnel responsible for performing validation

Answer 15

• Should be established and their commitment to sustain continued validation status should be documented.
• All validation reports should summarise the results and should also be documented appropriately.

Question 16

In GMP what is good documentation a part of?

Answer 16

• Essential part of the quality assurance system and it is important to working in compliance with GMP standards

Question 17

What should the manufacturer’s Quality Management System define and what formats may the documentation be in?

Answer 17

• Should define the different types of documents and media used.
• Documentation can be presented in various types such as paper-based, electron and photographic media

Question 18

What is the main objective of the Quality Management System?

What should this system include?

Answer 18

• Ensure that all activities are controlled, monitored and recorded, which directly or indirectly affect aspects of the quality of medicinal products
• Include adequate instructions concerning GMP requirements, in addition to providing adequate recordings of the dfferient processes and observations made, so that compliance to the GMP requirements can be verified

Question 19

What are the main types of documents used to manage and record GMP compliance?

Answer 19

• There are two main types of documentation used to manage and record GMP compliance: (1) instructions and (2) records

Question 20

What should Instruction Documentation include?

Answer 20

• Specifications: basis for quality evaluation, it describes the requirements that must be conformed to, concerning the handling of products or materials.
• Manufacturing Formulae: Describes all the starting materials, equipment and computerised systems to be used and specifies all processes, packaging, sampling and testing instructions.
• Standard Operating Procedures
• Protocols
• Technical agreements

Question 21

What should the record/report documentation include?

Answer 21

• Records: provide proof of the different activities performed in the manufacturing process, which also provides evidence for compliance with GMP standard.
• Certificates of Analysis: provides an overview of testing results on samples of products or materials.

Question 22

What are good documentation practices?

Answer 22

• Appropriate controls should be implemented to ensure that the integrity, accuracy, legibility and availability of documents are maintained. Instruction documents should not contain any errors, as this may compromise compliance with GMP standards.

Question 23

What are some additional points to consider with regards good documentation practice?

Answer 23

• Records should be taken at the time each activity is conducted, which will ensure that all relevant activities related to the manufacture of medicinal products are traceable.
• Any adaptions made to the documents in the Quality Management System must be signed and dated, and where applicable, the explanation of the alternations should also be recorded.

Question 24

Describe the GMP requirements for the retention of documents

Answer 24

• Records relating to each manufacturing activity must be clear and succinct.
• Controls must be in place to ensure that the records taken can be validated. E.g., there are specific requirements for the relation of batch documentation, which must be retained for a specific period of time even after the batch has expired, for traceability purposes.
• Other requirements may be specified in the marketing legislation related to the specific types of products being manufactured.

Question 25

Describe GMP documentation for batch processing and what it should be based on

Answer 25

• A record should be kept for batch processing.
• It should be based on the relevant aspects of the currently approved Manufacturing Formula and Processing Instructions

Question 26

What information should documentation for batch processing include?

Answer 26

• Name and batch number of the product
• Dates and times of significant intermediate stages during production
• Identification of the operators who carried out each step in the manufacturing process
• Records the batch number and the quantities of any recovered or reprocessed material.
• Mmajor equipment used in production
• A record of the in-process controls
• The product yield obtained
• Records of all deviations made from the Manufacturing Formula and Processing instructions

Question 27

What is the batch packaging record and what should it include?

Answer 27

• Should be logged for each batch and should be based on the packaging instructions. The batch packaging record should contain the following points:
  
  • The name and batch number of the product
  • The date and times of the packaging process
  • Identification of the operator(s) who conducted each relevant step in the packaging operation and conformity with the packaging instructions
  • The quantities and reference numbers of packaging materials

Question 28

List some additional GMP reports and documentation

Answer 28

• xTesting procedures
• Starting and packaging materials
• Equipment assembly and calibration
• Maintenance and sanitation
• Technology transfer
• Environmental conditions
• Pest control
• Returns of the product
• GMP compliance audits
• Supplier audits
• Complaints

Question 29

Outline briefly GMP production operations

Answer 29

• Production operations must follow the defined procedures and the principles of GMP, in order to produce products to a high standard of quality and to be compliant with the relevant manufacturing and marketing authorisations.

Question 30

GMP production operations, consider:

Access to premises

Answer 30

• Should be access restrictions to the production premises, permitting only authorised personnel to enter.

Question 31

GMP production operations, consider:

Handling of materials and products

Answer 31

• All handling of materials and products, such as sampling, labelling, processing, packaging and distribution should be performed in accordance with applicable procedures and/or instructions.

Question 32

GMP production operations, consider:

Allocation of areas

Answer 32

• In most cases, non-medicinal products should not be produced in the areas (or with the same equipment) used for the production of medicinal products

Question 33

GMP production operations, consider:

Quarantine

Answer 33

• All incoming materials and finished products should be quarantined after receipt or processing.

Question 34

GMP production operations, consider:

Storage

Answer 34

• All materials and products should be stored under the correct conditions.

Question 35

GMP production operations, consider:

Labels

Answer 35

• Legible labels should be applies to materials, products, containers and equipment.

Question 36

GMP production operations, consider:

Changes to manufacturing process

Answer 36

• Significant changes to the manufacturing process, including amendments to the equipment or materials, which may alter the quality of the product and/or reproducibility of the process, should be validated.

Question 37

GMP production operations, consider:

How to reinforce GMP

Processes and procedures

Cross contamination

Answer 37

• Validation studies should reinforce GMP.
• Processes and procedures should be routinely re-validated to ensure that they are still able to perform their intended use and capable of manufacturing high quality medicinal products.
• Cross-contamination should be avoided by appropriate technical or organisational measures.

Question 38

GMP production operations, consider:

Controls

Storage of intermediate and bulk products

Completion of the manufacturing process

Answer 38

• All relevant in-process controls and environmental controls should be performed and recorded.
• Intermediate and bulk products should be kept under suitable conditions.
• Upon the completion of manufacturing the products, the products should be help in quarantine until their release, under specific conditions, established by the manufacturer.

Question 39

In accordance with GMP what are the requirements for subcontractin work?

What should the contract outline?

Answer 39

• any activities that are subcontracted (outsourced) should be defined, agreed and regulated to avoid misunderstandings, which may affect the quality of the finished product.
• A formal contract between the contract giver and the subcontractor should be employed, defining the responsibilities of each party.

Question 40

With regards GMP subcontracted activites, what are the responsabilities of the contract giver?

Answer 40

• contract giver’s responsibility to assess the legality, suitability and the competence of the subcontractor to perform the outsourced activities

Question 41

With regards GMP subcontracted activites, describe what must happen for the subcontractor to introduce changes and what this means for the contract giver

Answer 41

• If the subcontractor introduces any changes in technical or other arrangements, they must be in compliance with the relevant marketing authorisation committee.
• Therefore, the contract giver should regularly review the performance of the subcontractor and suggest correction strategies if needed.

Question 42

Briefly describe the practices in the manufacturing of sterile medicinal products

Answer 42

• The EU Guide to GMP provides additional guidance on manufacturing sterile medicinal products using aseptic processing.
• Manufacturing sterile products requires special measures in order to diminish risks of microbiological contamination and pyrogen contamination.
• This type of manufacturing must abide to strictly following validated methods of preparation

Question 43

With regards practices in the manufacturing of sterile medicinal products, consider:

Where the medicinal product is manufactured

Answer 43

• The manufacture of sterile medicinal products should be performed in designated clean areas, which should be airlocked.

Question 44

With regards practices in the manufacturing of sterile medicinal products, consider:

The two types of manufacturing operations

Answer 44

Two main groups:

1. where the product is terminally sterilised and
2. those which are aseptic processes.

Both types of operations should be conducted in distinct areas.

Question 45

With regards practices in the manufacturing of sterile medicinal products, consider:

Environmental cleanliness

Answer 45

• Each manufacturing system requires a suitable degree of environmental cleanliness, in order to minimise the risk of microbial contamination.
• Each clean room has two distinct states to reach the desired air-cleanliness level.

Question 46

With regards practices in the manufacturing of sterile medicinal products, consider:

The two states of a clean room

Answer 46

1. “at-rest” state is the condition where the operating equipment is installed and operating, in the absence of operating personnel.
2. “in operation” state is the condition where the installation is functioning in the defined operating mode, in the presence of specified operating personnel.

• These two states should be well-defined for each clean room.

Question 47

With regards practices in the manufacturing of sterile medicinal products, consider:

The distinguishable grades for the manufacture of sterile medicinal products,

Answer 47

There are 4 distinguishable grades:

• Grade A: This zone is for high-risk operations, usually operated under laminar air flow systems.
• Grade B: This zone is classified as the background area for the grade A zone used for aseptic preparation and filling.
• Grade C and D: This is the clean area for performing less critical processes in the manufacture of sterile products.

Question 48

With regards practices in the manufacturing of sterile medicinal products, consider:

Monitoring of designated areas

Answer 48

• During operation, the designated areas should be regularly monitored, in order to regulate cleanliness of the different grades.

Question 49

With regards practices in the manufacturing of sterile medicinal products, consider:

The monitoring of aspetic areas

Answer 49

• Areas used for aseptic processing, should be frequently monitored using techniques such as settle plates, volumetric air and swabs of the surfaces.
• The results generated should be reflected upon when assessing batch documentation for the release of finished medicinal products.
• Note that further microbiological monitoring is also needed beyond production operations, such as sanitisation and validation of systems.

Question 50

With regards practices in the manufacturing of sterile medicinal products, consider:

Microbiological monitoring

Answer 50

• There should be alert and action limits in place for microbiological monitoring. If these restrictions are surpasses, corrective procedures should be implemented.

Question 51

With regards GMP premesis and equipement, describe their arrangement

Answer 51

• Premises and equipment must be situated, designed, adapted and maintained to complement the operational procedures.
• The arrangements should be designed to minimise the risk of errors and allow general maintenance procedures to be performed to prevent cross-contamination from affecting the quality of the products.

Question 52

With regards GMP premesis and equipement, describe how cross-contamination is prevented

Answer 52

• To prevent cross-contamination in the production area, specified facilities must be available for the manufacturing of specific products and different measures may be taken for the production of pharmaceutical and medicinal products

Question 53

With regards GMP premesis and equipement, describe the separation of areas

Answer 53

• Quality Control laboratories are separate from production areas, which are very important for laboratories concerned with the control of radioisotpes, biological and microbiological material, which may need to be kept separate from each other.
• Refreshment rooms must be separate from other designated areas

Question 54

With regards GMP premesis and equipement, describe storage areas

Answer 54

• Careful consideration is also required for storage areas, which must be of adequate capacity to permit orderly storage of different categories of material and products such as: starting and packaging materials, intermediate, bulk and completed products, products in quarantine and products that have been recalled.

Question 55

With regards GMP premesis and equipement, outline the considerations for the equipment

Answer 55

• Manufacturing equipment should also be designed, arranged and maintained in order to perform its specific function.
• Cleaning, repair and general maintenance of equipment is very important and should be performed in accordance to the written procedures.
• Important to ensure that the production equipment does not alter or serve as a hazard to the products.

Question 56

With regards GMP, briefly describe the handling of complaints and product recalls and what the implication of this is

Answer 56

• In accordance to written procedures, all complaints and related information concerning a defective product must be carefully reviewed.
• Means that an effective system must be in place to address product recalls, which are suspected/known to be defective, which have been supplied to the market.

Question 57

With regards GMP, who is responsible for handling complaints and recalls?

What support may this person receive?

Answer 57

• A qualified person should be assigned with the responsibility for addressing complaints and determining the appropriate measure to take.
• This person should be supported by related staff members, to address all the aspects of the product recall

Question 58

With regards GMP handling of recalls and complaints, describe the procedures and how their effectiveness is ensured

Answer 58

• written procedures should be place describing the action to be taken.
• Recall operations therefore need to be effective and ready to undergo such operations at any time.
  
  • the effectiveness of product recall procedures needs to be evaluated regularly.

Question 59

With regards GMP handling of recalls and complaints, describe the process after having received a complaint

Answer 59

• All complaints concerning a defective product should be recorded (and references to the corresponding batch records) to permit a thorough investigation, which typically involves Quality Control personnel.
• When a defective product is detected, action should be taken to check other batches to determine whether they are also affected.
• Other issues to consider, is whether a complaint was made due to counterfeiting.

Question 60

Describe GMP aseptic preparation

Answer 60

• Grade A and grade B environments should be used for handling of sterile starting materials and specific apparatuses, providing that they are not exposed to sterilisation and filtration.
• grade C zone used for the preparation of solutions, which are subjected to sterile filtration.
• After washing the apparatuses, the components should be handled in a grade D zone.
• Handling and filling of aseptically prepared products should be performed in a grade A zone (with a grade B background)

Question 61

Describe GMP sanitation

Answer 61

• The sanitation of designated clean areas is very important.
• More than one type of disinfectants should be used and the different types of disinfectants and detergents employed, should be monitored for microbial contamination.
• Fumigation of clean areas may be helpful for minimising microbiological contamination in unreachable areas.

Question 62

Describe GMP sterilisation - what it must comply with and what it must demonstrate

Answer 62

• Sterilisation procedures should be validated.
• Must comply with marketing and manufacturing authorisations.
• Physical methods and biological indicators should be used to demonstrate the suitability of sterilisation processes for the manufacture of medicinal products and its efficiency and effectiveness in achieving the required sterilising conditions.

Question 63

Describe GMP sterilisation - what are the different types of sterilisation

Answer 63

• Different types of sterilisation techniques include heat sterilisation, radiation sterilisation and sterilisation with ethylene oxide.
• Where applicable, heat sterilisation is the preferred method.

Question 64

Describe GMP sterilisation, further describe biological indicators

Answer 64

• If biological indicators are used as an additional method for monitoring sterilisations, caution should be taken to avoid transferring microbial contamination

Question 65

Describe GMP sterilisation records

Answer 65

• Taking records of each sterilisation run is recommended because they may need to be approved as part of the batch release procedure.

Question 66

Describe GMP equipment preparations

Answer 66

• Planned maintenance and validation is recommended for all equipment such as filtration systems, sterilisers, air vents, and water treatment.
• Installation and fittings of practicable equipment should be designed in a way, which ensures that maintenance and repairs can be performed outside of the clean zones.
  
  • If this is unavoidable, sterilisation is highly recommended.