Clean Room and GMP Quiz

Version 13 of the PIC/s PE-009 Guide to Good Manufacturing Practice was adopted by the TGA from 01^st January 2019. This replaced Version 8 of PE-009 that had been adopted in 2010.

The GMP reference is PE-009-13 Chapter 1 Pharmaceutical Quality System, Clause 1.3 “The size and complexity of the company’s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one. The design of the system should incorporate appropriate risk management principles including the use of appropriate tools. While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated at the site level.”

The GMP reference is PE-009-13 Part 1 Chapter 1 Pharmaceutical Quality System, Clause 1.12 “Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively.”

The GMP reference is PE-009-13 Part 1 Chapter 2: Personnel, Clause 2.4 “Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place to achieve the quality objectives, and, that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organisation. Senior management should establish a quality policy that describes the overall intentions and direction of the company related to quality and should ensure continuing suitability and effectiveness of the Pharmaceutical Quality System and GMP compliance through participation in management review.”

The GMP clause is PE009-013 Part 1 Chapter 2: Personnel, Clause 2.12 “Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, should be given specific training.”

The GMP clause is PE009-13 Part 1 Chapter 2: Personnel, Clause 2.22 “ Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the annexes.”

The Annexes cover specific requirements for different manufacturing processes, for example:

Annex 1: Manufacture of Sterile Medicinal Products
Annex 2: Manufacture of Biological medicinal substances and Products
Annex 3: Manufacture of radiopharmaceuticals
Annex 6: Manufacture of Medicinal Gases

The GMP Clause is PE-009-13 Part 1 Chapter 3: Premises and Equipment, Clause 3.23 “Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.”

The GMP clause is PE009-013 Part 1, Chapter 3: Premises and Equipment, Clause 3.42 “Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow”

The GMP clause is PE-009-013 part 1, Chapter 4: Documentation, clause 4.11 “Specific requirements apply to batch documentation which must be kept for one year after expiry of the batch to which it relates or at least five years after certification of the batch by the Authorised Person, whichever is the longer. For investigational medicinal products, the batch documentation must be kept for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used. Other requirements for retention of documentation may be described in legislation in relation to specific types of product (e.g. Advanced Therapy Medicinal Products) and specify that longer retention periods be applied to certain documents.”

The GMP Clause is PE009-013 Part 1, Chapter 5: Production, Clause 5.33 “Each dispensed material and its weight or volume should be independently checked and the check recorded.”

The GMP clause is PE-009-013 Part 1, Chapter 5: Production,  Clause 5.44 “When setting up a programme for the packaging operations, particular attention should be given to minimising the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.”

The correct GMP clause is PE009-013 Chapter 5: Production, clause 5.57 “. Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if uncoded printed materials are returned to stock.”

The correct GMP clause is PE009-013, chapter 7: Outsourced Activities, clause 7.7 “The Contract Acceptor should ensure that all products, materials and knowledge delivered to him/her are suitable for their intended purpose.”

The GMP Clause is PE009-013, Chapter 8: Complaints and Recalls, Clause 8.8 “The Competent Authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, detection of counterfeiting or any other serious quality problems with a product”

The GMP clause is PE009-013, Chapter 8: Complaints and Product Recall, clause 8.11: “Recall operations should be capable of being initiated promptly and at any time”

Correct!

GMP reference: PE 009-13, Part I, Chapter 1 Pharmaceutical Quality System, 1.4, page 3

“(xiv) An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems.

This can be determined using Quality Risk Management principles. In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present. Appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 1 Pharmaceutical Quality System, 1.6, page 3

“There should be periodic management review, with the involvement of senior management, of the operation of the Pharmaceutical Quality System to identify opportunities for continual improvement of products, processes and the system itself”.

Correct! The GMP reference is GMP reference PE 009-13, Part I, Chapter 1 Product Quality Review, 1.10, page 6
“A review of starting materials including packaging materials used in the product, especially those from new sources and in particular the review of supply chain traceability of active substances”

PE009-13, the PIC/S guide to GMP for medicinal products TGA interpretation and expectations for demonstrating compliance:

“Manufacturers of dosage forms should have a clear understanding of the approved suppliers of active substances, and each entity and their responsibility in the supply chain between the site of manufacture and receipt (clause 1.10(i)). Supply chains should be adequately secure, integral and ensure that materials are transported under appropriate conditions. Supply chains should be mapped and any identified risks managed following the principles of quality risk management.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 2 Personnel, 2.11, page 11

“Besides the basic training on the theory and practice of the Pharmaceutical Quality System and Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept.”

Correct! The GMP reference is Refer to PE 009-13, Part I, Chapter 7 Outsourced Activities, 7.4, page 40

“The Pharmaceutical Quality System of the Contract Giver should include the control and review of any outsourced activities”

PE009-13, the PIC/S guide to GMP for medicinal products TGA interpretation and expectations for demonstrating compliance

“The title of chapter 7 has changed from ‘Contract manufacturer and analysis’ to ‘Outsourced activities’ in recognition of the fact that there are a number of outsourced (contracted) activities that may have a direct effect on the quality of medicinal product manufactured by a site. The previous title of the chapter restricted the extent of GMP controls to only outsourced manufacturing and testing services and thus did not appropriately manage the risk associated with other outsourced activities. Examples of outsourced activities that this chapter would now apply to include, but are not limited to:

-Contract manufacturing and analysis

-Maintenance and calibration services

-Providers of critical consumables, e.g. gowns, sterilised componentry

-Suppliers and manufacturers of raw materials, packaging materials and printed artwork

-Provision of training and consulting services

-Validation services associated with facilities, equipment, utilities, process and product design, qualification and validation

-Provision of transport and logistical services for products

-Contract cleaning and waste management services

-Contract pest control services

-Agencies that provide temporary or contract personnel”

Correct! The GMP reference is PE 009-13, Part I, Chapter 2 Personnel, 2.23, page 12

“Consultants should have adequate education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants”.

Correct! The GMP reference is PE 009-13, Part I, Chapter 3 Premise and equipment, 3.41, page 16

“Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 4 Documentation, 4.1, page 18

“All types of document should be defined and adhered to. The requirements apply equally to all forms of document media types. Complex systems need to be understood, well documented, validated, and adequate controls should be in place. Many documents (instructions and/or records) may exist in hybrid forms, i.e. some elements as electronic and others as paper based. Relationships and control measures for master documents, official copies, data handling and records need to be stated for both hybrid and homogenous systems. Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented. Appropriate controls should be in place to ensure the integrity of the record throughout the retention period.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 4 Documentation, 4.8, page 19

“Records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 4 Documentation, 4.29, page 25

“There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples:

– Validation and qualification of processes, equipment and systems;
– Equipment assembly and calibration;
– Technology transfer;
– Maintenance, cleaning and sanitation;
– Personnel matters including signature lists, training in GMP and technical matters, clothing and hygiene and verification of the effectiveness of training;
– Environmental monitoring;
– Pest control;
– Complaints;
– Recalls;
– Returns;
– Change control;
– Investigations into deviations and non-conformances;
– Internal quality/GMP compliance audits;
– Summaries of records where appropriate (e.g. product quality review);
– Supplier audits.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 6 Quality control, 6.19, page 36

“Special attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards and culture media. They should be prepared and controlled in accordance with written procedures. The level of controls should be commensurate to their use and to the available stability data.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 7 Outsourced activities, 7.1, page 40

“There should be a written contract covering the outsourced activities, the products or operations to which they are related, and any technical arrangements made in connection with it.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 9 Self inspection, 9.1, page 45

“Personnel matters, premises, equipment, documentation, production, quality control, distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self inspection, should be examined at intervals following a pre-arranged programme in order to verify their conformity with the principles of Quality Assurance.”

Correct! PE 009-13, Part I, Chapter 1 Pharmaceutical Quality System, 1.4, page 3

““(xiv) An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems. This can be determined using Quality Risk Management principles. In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present. Appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles;”

Correct! The GMP reference is PE 009-13, Part I, Chapter 1 Pharmaceutical Quality System, 1.8, page 5

“(xi) Complaints about products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent reoccurrence.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 2 Personnel, 2.9, page 10-11

“The heads of Production, Quality Control and where relevant, Head of Quality Assurance or Head of Quality Unit, generally have some shared, or jointly exercised, responsibilities relating to quality including in particular the design, effective implementation, monitoring and maintenance of the Pharmaceutical Quality System. These may include, subject to any national regulations:

(i) The authorisation of written procedures and other documents, including amendments;
(ii) The monitoring and control of the manufacturing environment;
(iii) Plant hygiene;
(iv) Process validation;
(v) Training;
(vi) The approval and monitoring of suppliers of materials;
(vii) The approval and monitoring of contract manufacturers and providers of other GMP related outsourced activities;
(viii) The designation and monitoring of storage conditions for materials and products;
(ix) The retention of records;
(x) The monitoring of compliance with the requirements of Good Manufacturing Practice;
(xi) The inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality;
(xii) Participation in management reviews of process performance, product quality and of the Pharmaceutical Quality System and advocating continual improvement;
(xiii) Ensuring that a timely and effective communication and escalation process exists to raise quality issues to the appropriate levels of management.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 2 Personnel, 2.11, page 11

“Besides the basic training on the theory and practice of the Pharmaceutical Quality System and Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 3 Premise and equipment, 3.19, page 15

“Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 3 Premise and equipment, 3.34, page 16

“Manufacturing equipment should be designed, located and maintained to suit its intended purpose.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 3 Premise and equipment, 3.41, page 16

“Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 4 Documentation, 4.1, page 18

“All types of document should be defined and adhered to. The requirements apply equally to all forms of document media types. Complex systems need to be understood, well documented, validated, and adequate controls should be in place. Many documents (instructions and/or records) may exist in hybrid forms, i.e. some elements as electronic and others as paper based. Relationships and control measures for master documents, official copies, data handling and records need to be stated for both hybrid and homogenous systems. Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented. Appropriate controls should be in place to ensure the integrity of the record throughout the retention period.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 4 Documentation, 4.8, page 19

“Records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 5 Production- General, 5.10, page 25

“There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples:

– Validation and qualification of processes, equipment and systems;
– Equipment assembly and calibration;
– Technology transfer;
– Maintenance, cleaning and sanitation;
– Personnel matters including signature lists, training in GMP and technical matters, clothing and hygiene and verification of the effectiveness of training;
– Environmental monitoring;
– Pest control;
– Complaints;
– Recalls;
– Returns;
– Change control;
– Investigations into deviations and non-conformances;
– Internal quality/GMP compliance audits;
– Summaries of records where appropriate (e.g. product quality review);
– Supplier audits.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 5 Production, 5.19, page 27-8

“Cross-contamination should be avoided by appropriate technical or organisational measures, for example:

1. a) Production in segregated areas (required for products such as penicillins, live vaccines, live bacterial preparations and some other biologicals), or by campaign (separation in time) followed by appropriate cleaning;
2. b) Providing appropriate air-locks and air extraction;
3. c) Minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air;
4. d) Keeping protective clothing inside areas where products with special risk of cross-contamination are processed;
5. e) Using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination;
6. f) Using “closed systems” of production;

g) Testing for residues and use of cleaning status labels on equipment.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 6 Quality control, 6.19, page 36

“Special attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards and culture media. They should be prepared and controlled in accordance with written procedures. The level of controls should be commensurate to their use and to the available stability data.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 7 Outsourced activities, 7.1, page 40

“There should be a written contract covering the outsourced activities, the products or operations to which they are related, and any technical arrangements made in connection with it.”

Correct! The GMP reference is PE 009-13, Part I, Chapter 9 Self inspection, 9.1, page 45

“Personnel matters, premises, equipment, documentation, production, quality control, distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self inspection, should be examined at intervals following a pre-arranged programme in order to verify their conformity with the principles of Quality Assurance.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 9 Self Inspection, Principle section, page 43.

“Self inspections should be conducted in order to monitor the implementation and compliance with Good Manufacturing Practice principles and to propose necessary corrective measures.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 2 Personnel- Key Personnel, 2.3, page 7.

“Key Personnel includes the head of Production, the head of Quality Control, and if at least one of these persons is not responsible for the release of products the authorised person(s) designated for the purpose. Normally key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 1 Quality Management- Quality Risk Management, 1.6, page 5.

Correct! The GMP reference is PE 009-12, Part I, Chapter 2, Personnel- Training, 2.11, page 9

“Visitors or untrained personnel should, preferably, not be taken into the production and Quality Control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 2 Personnel- Personnel Hygiene, 2.16, page 10

“Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 3 Premises and Equipment- General, 3.5, page 11

“Steps should be taken in order to prevent the entry of unauthorised people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 4 Documentation- Good Documentation Practices, 4.9, page 17

“Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 4 Documentation- Specifications, 4.13, page 18

“There should be appropriately authorised and dated specifications for starting and packaging materials, and finished products.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 4 Documentation – Procedures and Records, 4.28, page 23

“Records should be maintained for the distribution of each batch of a product in order to facilitate recall of any batch, if necessary.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 5 Production- General, 5.10, page 25

“At every stage of processing, products and materials should be protected from microbial and other contamination.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 5 Production- Prevention of Cross-Contamination in Production, 5.20, page 27

“Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 5 Production- Starting Materials, 5.29, page 28

“Labels should bear at least the following information:
       the designated name of the product and the internal code reference where applicable;
       a batch number given at receipt;
       where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected);
       where appropriate, an expiry date or a date beyond which retesting is necessary.
When fully computerised storage systems are used, all the above information should not necessarily be in a legible form on the label.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 6 Quality Control- On-going stability programme, 6.32, page 37

“Out of specification or significant atypical trends should be investigated. Any confirmed out of specification result, or significant negative trend, should be reported to the relevant competent authorities. The possible impact on batches on the market should be considered in accordance with chapter 8 of the GMP Guide and in consultation with the relevant competent authorities.”

Correct! The GMP reference is PE 009-12, Part I, Chapter 3 Premises and equipment- Storage Areas, 3.18-3.20, page 13

“3.18 – Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled.
3.19 – Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.
3.20 – Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.”

The number of air changes will depend on the room classification and the level of activity conducted within the room. Guidance figures of a room recovery within 10-15 minutes are provided in PE009-12 Annex 1.

Clean rooms still need to meet relevant local health, safety and environmental regulations

PIC/S PE009-12 makes no reference to the use of gloves in a Grade C or D area, however for Grade A/B:  Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body.

You should be concerned about the fire rating problems with EPS. More fire resistant materials including polyisocyanourate (PIR) are available on the market. We recommend discussing with a specialist or your insurer.

PIC/S PE009-12 Annex 1 Section 48 “False ceilings should be sealed to prevent contamination from the space above them”

Limits are:

3,520,000 particles/m3 @ 0.5 micron

29,000 particles/m3 @ 5.0 micron

Clause 3.10 Chapter 3 PIC/S PE009-12 (Part I)

PIC/S PE009-12 (Part I) Chapter 3 Clause 3.10

PIC/S PE009-12 (Parts I and II)

AS/ISO 14644.4:2002