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GMP in Practice: 24 chapters written by internationally renowned industry experts.

 

GMP Regulations: 8 chapters with the most important GMP guidelines and regulations.

 

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Updates Forecast & History

2016-12-01

GMP MANUAL Update No. 27 (online version only)

With this GMP MANUAL UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

GMP in Practice

3.F
Building Services
6.C

Qualification documentation

7.A
Official requirements and agency expectations
7.D
Validation documentation
9.H
Validation of Excel applications
11.G
Weighing
18.F Self-inspection


GMP Regulations

C.8.5.1
Importation of Active Substances for Medicinal Products for Human Use, Q&A, Version 7
D.1.6 21
CFR 600
D.1.7 21
CFR 606
D.1.8 21
CFR 680
D.1.9 21
CFR 601
D.23
Submission of Quality Metrics Data, Revision 1, DRAFT
D.23.1 Quality Metrics Technical Conformance Guide, Version 1.0, DRAFT

 

GMP in Practice

Chapter 3 Premises

3.F Building Services

Building services is an umbrella term for a number of different supply and disposal systems for rooms and facilities. Requirements for a GMP-compliant implementation of technical building installations can be found in the EU GMP Guidelines. They deal mainly with the importance of easy cleanability and accessibility. The installations themselves should never be a source of contamination. Manufacturing areas are heated using the ventilation system. Hygiene radiators may be used in ancillary areas. The ventilation system is an integral part of building services. A distinction is drawn between make-up units and recirculation units. The leaktightness of rooms is a decisive factor in maintaining the pressure cascade. Cooling systems are used to supply process and infrastructural systems. The formation of condensation should be avoided, if possible. Hygiene is of the utmost importance for plumbing with a view to preventing microbial contamination. Special attention should be given to the treatment and disposal of wastewater. Electrical, instrumentation and control technology are now part and parcel of modern pharmaceutical manufacturing and affect all areas of building services. Control cabinets should be placed in technical areas. Systems for monitoring quality-related parameters are subject to the qualification requirements for computerised systems. Building automation is the umbrella term for all of the regulation, control, and monitoring technology in a building. A distinction should be made between local control and central visualisation. All GMP-related technical building systems must be qualified in accordance with the requirements in Annex 15. (Thomas Schreiner, Olaf Stoll)

Chapter 6 Qualification

6.C Qualification documentation

All qualification activities must be documented in writing because they would otherwise not provide proper evidence of the equipment status. The qualification documentation comprises the qualification master plan and the qualification plans and reports. In this chapter the requirements for form and content of the qualification documents are described. To ensure that the overview is not lost in large-scale projects it is important not only to ensure that each document is set up in a clear manner but also that the document structure of the entire qualification documentation be defined to have a clear set-up. This is illustrated concretely using various models. (Thomas Peither)

Chapter 7 Process Validation

7.A Official requirements and agency expectations

Process validation is part of the quality assurance system and should prove that the procedures and processes used during the manufacture of medicinal products are suitable for their purpose. In Production, the Head of Production is responsible for process validation. He/she can delegate the implementation but not the responsibility. Every process validation is based on previously defined acceptance criteria for the critical quality attributes and process parameters which are determined and specified during the process development and process optimisation phases. Processes should be designed in such a way that they can be monitored and controlled. Traditional process validation is generally carried out prospectively. Under certain circumstances, a concurrent approach can be taken for existing processes. In the case of processes that were developed taking a quality-by-design approach, continuous process verification can be carried out. (Michael Hiob, PhD)

7.D Validation documentation

The validation master plan (VMP) is a comprehensive document that describes the individual validation strategy of a company and is used for structuring and controlling validation activities. The approach taken to validation projects, the responsible persons and company-specific terminology are defined in the VMP. The VMP can be structured in different ways depending on the scope of application. For example , a VMP can relate to a complete company or to a single product. The VMP supports internal and external communication. The approach to a validation study is defined in detail in the validation protocol. In addition to a precise description of the process itself, IPC, quality attributes, equipment, starting materials, analytic methods, test plans, samples and acceptance criteria, the time schedule, responsibilities and evaluation methods are defined. The data collected during the manufacture and testing of the validation batches is evaluated in the validation report and compared with the requirements in the validation protocol (acceptance criteria). Based on these results, a conclusion is drawn and it is documented whether the examined process, depending on the respective validation phase, can be considered validated, or whether additional activities (e. g. process optimisation, close monitoring, manufacture of additional validation batches, etc.) are required before the next validation phase/step begins. (Christine Oechslein, PhD)

Chapter 9 Computer System Validation

9.H Validation of Excel applications

An extremely wide spectrum of applications can be realised in Excel involving more or less effort. If macros are used, the possibilities are almost infinite. It is important that these applications function properly and are reliable, especially with regard to data storage, and that they comply with the regulations. Excel applications remain applications that are not very well-documented or validated. Excel developers are often self-taught developers who are very good at what they do, but they often lack a professional approach. Excel applications are still widely used in quality control, development and validation and also as adhoc applications, e. g. for troubleshooting. The following should be considered:

  • the know-how for creating GxP-compliant Excel applications should be improved
  • standardised procedures should be established for the most important types of Excel applications to ensure that workflows are adhered to and streamlining facilitate
  • forms should be developed that make documentation easier
  • tools should be used that make it easier for users to plan the validation, implementation and documentation of the tests and to document the Excel worksheets (templates)

The requirements for Excel applications in the GMP Guidelines have to be implemented based on risk-based evaluations. This chapter shows how to reduce the effort required for successful implementation to a minimum and to ensure compliant applications that will pass inspection. (Thomas Trantow, PHD, et al.)

Chapter 11 Production

11.G Weighing

The weighing process is a sensitive part of the process chain, because mistakes that are made here cannot be corrected at a later stage. During weighing, two aspects are focused on:

  • The accuracy of the weighing process (qualitative and quantitative)
  • The prevention of (cross) contamination and mix-ups

Structural and organisational guidelines should be used to minimise risk during weighing.

Different principles can be used during weighing: a distinction is made, for example, between additive weighing where all of the raw materials for one order are weighed in a single container, and individual weighing where each raw material is weighed separately. In addition, depending on the number of raw materials used, a decision must be made whether to carry out order-based weighing or raw material-based weighing. Further distinguishing criteria include the location of the weighing room (central/decentralised), the mode of implementation (manual/automatic) and the material flow (vertical/ horizontal).

Validated computerised systems provide a high level of safety. Only raw materials clearly specified in the manufacturing instruction and containers that have been approved can be weighed.

Weighing areas are subject to special requirements that have to be checked during qualification. These include the location and design of the rooms, and especially the technical measures carried out to prevent emissions and contamination. When balances are chosen, technical aspects such as resolution, accuracy and weighing range must be taken into consideration in addition to specific design features. The installation location should be protected against draughts, sunlight and vibration. The function of balances must be checked and documented on a regular basis. A distinction is made between a daily check of the weighing range and, for example, a monthly calibration of the entire operating range.

The weighing process must be specified in written form from the delivery of the starting materials to provision for Production. Every weighing process must be recorded so that proof can be provided at all times that the process was carried out properly. (Christian Gausepohl, PhD)

Chapter 18 Inspection

18.F Self-inspection

Self-inspections are not only used to monitor quality levels, but for continuous improvement also because they can also be used to identify potential risks and areas of improvement. This requires that all parties involved display a high level of awareness and communicate openly. Self-inspections have to be planned, carried out and documented in accordance with written procedures. If deficiencies are detected, they should be evaluated and eliminated using a standardised process. It makes sense to use a classification scheme that is similar to that used during official inspections and audits to facilitate comparability. If selfinspections are planned meticulously and carried out using checklists or aidemémoires, they are a meaningful and effective way of checking GMP status and ensuring continuous quality improvement. (Christian Gausepohl, PhD)

GMP Regulations

Chapter C EU Directives and Guidelines

C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use, Q&A, Version 7

This document is continuously updated and further supplemented.

With this new version, Q&A 35 was added. It clarifies the requirements in case of importation of active substances released for sale before the expiration date of their written confirmation but only imported into the EU once the written confirmation had been expired.

Furthermore, a minor editing of Q&A 10A and 29A was carried out and Q&A 29B (obsolete) was deleted.

Chapter D USA: CFR and FDA Guidelines

D.1.6 21 CFR 600 Biological Products

New section 600.82 Notification of a permanent discontinuance or an interruption in manufacturing in subpart D has been affiliated.

D.1.7 21 CFR 606 GMP for Blood and Blood Components

New section 606.145 Control of bacterial contamination of platelets in subpart H has been affiliated.

The following changes to the text have been made:

  • The word “suitability“ has been changed to “eligibility”
  • Subpart F, Sec. 606.100, b) introduction text has been changed
  • Subpart F, Sec. 606.100, b), 20) has been shortened
  • Subpart F, Sec. 606.100, b), 21) + 22) new points have been added
  • Subpart F, Sec. 606.110, a), 2) “qualified licensed physician” changed to: “responsible physician”
  • Subpart F, Sec. 606.110, a), 2) “certified in writing” changed to: “determined and documented”
  • Subpart G, Sec. 606.121, c), 11)+12) “communicable disease agents” changed to: “relevant transfusion-transmitted infections”
  • Subpart G, Sec. 606.121, i), 5) “communicable disease agents” changed to: “relevant transfusion-transmitted infections”
  • Subpart G, Sec. 606.122, e) “communicable disease agents” changed to: “relevant transfusion-transmitted infections”
  • Subpart G, Sec. 606.160, b), ix) has been shortened
  • Subpart G, Sec. 606.160, b), xi) has been changed
In the following sections references to other CFRs have been changed:
  • Subpart F, Sec. 606.100, b), 19)
  • Subpart F, Sec. 606.110, a), 2)
  • Subpart G, Sec. 606.121, h),2)+3)
  • Subpart G, Sec. 606.121, i), 5)
  • Subpart G, Sec. 606.160, b), viii)

D.1.8 21 CFR 680 Additional Standards for Miscellaneous Products

No amendments to the text, only change in date.

D.1.9 21 CFR 601 Licensing

No amendments to the text, only change in date.

D.23 Draft Guidance: Submission of Quality Metrics Data, Revision 1

On 23 November 2016, FDA released a Revision 1 of the draft guidance to Quality Metrics which was initially published in July 2015. The revision with the new title “Submission of Quality Metrics Data” came on short notice and is open for comments and suggestions until 24 January 2017.

The revised draft guidance describes FDA’s plans for an initial, voluntary phase of a quality metrics reporting program. FDA expects that this will allow the Agency to learn more about a limited set of quality metrics and associated analytics, and will help any future FDA decision-making about its quality metrics program. This second draft also provides an opportunity to gain additional perspectives from industry participants on the future use of quality metrics data.

FDA has reduced the number of metrics from four primary metrics and three optional metrics to three primary metric areas:

  • lot acceptance rate
  • invalidated out-of-specification rate
  • product quality complaint rate.

Additionally, FDA contemplates submission of either product reports segmented by site or site reports segmented by product which should be publicly recognized in a quality metrics reporters list.

The beginning of the voluntary phase of the quality metrics program is scheduled for early 2018.

D.23.1 Draft: Quality Metrics Technical Conformance Guide, Version 1.0

FDA has issued a 10-page technical specifications document providing recommendations on the submission of data to support quality metrics as part of the process validation lifecycle and pharmaceutical quality system assessment. The guide serves as the technical reference for implementation of the draft FDA guidance “Request for Quality Metrics” that was published in July 2015 and should be seen as a supplement.

The guide addresses:

  • Electronic submission – exchange format, file format
  • Data element specifications
  • Mandatory data elements and
  • Optional data elements
  • Data validation rules.

Data validation, regarding quality metrics, is defined as “a process that attempts to ensure that submitted data are both compliant and useful.” Furthermore, FDA says that “Data validation is one method used to assess submission data quality” and that “The data validation process can identify data issues early in the review that may adversely affect the use of the data.” It is pointed out that establishments should validate their metric data before submission using the posted validation rules and correct any validation errors.

Due to the only just published Revision 1 of the Draft Guidance on the Submission of Quality Metrics Data, a Version 2.0 of this Technical Conformance Guide can be expected soon.

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