GMP Compliance Adviser Update No. 7/2020

With this GMP Compliance Adviser 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

Chapter 0

Current topics


0.A Nitrosamines
0.A.1 Information on nitrosamine impurities
0.A.2 Nitrosamine impurities in medicines: What
have we learned? – EMA report 2020
0.A.3 Unpacking FDA's new guidance on controlling
nitrosamine impurities in drugs


Chapter 4

Facilities and Equipment

4.I Containment (personnel protection) for APIs,
solid oral dosage forms and bio-pharmaceutical


Chapter 13


13.B Packaging process  

GMP Regulations

Chapter C 

EU Directives and Guidelines

C.8.2.1 Safety features for medicinal products for human use – Questions and Answers – Version 18

C.19 Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products


GMP in Practice

Chapter 4 Facilities and equipment

4.I Containment (personnel protection) for APIs, solid oral dosage forms and bio-pharmaceutical products

The term “containment” is used in the API, pharmaceuticals and bio-pharmaceuticals industries to describe die enclosure of a process in which highly active substances are produced or handled. Containment has a dual role in its function serving both to ensure occupational safety for the operator and also protection of the product.

Containment systems may be divided into categories according to their workplace exposure limit. The connection between OEB (occupational exposure band), OEL (occupational exposure limit) as well as PDE (permitted daily exposure) and ADE (acceptable daily exposure) is illustrated in the containment pyramid. Here, the OEB corresponds to the containment grade OEL corresponds to the particle concentration in the workplace air and the PDE & ADE refer to the permitted amount which can be taken in by the operator or patient.

The effectiveness of the containment is checked by means of occupational safety control measurements. Special filter devices and measuring systems are positioned close to the operator and the containment system and evaluated after a defined exposure time.

The protection of the operator can be ensured in the simplest case by personal protective equipment. Laminar flow systems offer protection for employees, product and environment. Isolator systems offer the most comprehensive protection.

Isolators consist of a stainless steel housing with transfer systems for the inward and outward transfer of products, a glass panel with glove openings for the operator, as well as supply and exhaust air filters.

Apart from the use of isolators there are further constructive possibilities to realize containment. Various filling, emptying and transfer systems for drums, containers and containers are presented. The containment can be achieved by mechanical de-signs as well as by the use of protective foils.

Single-use systems represent another alternative. Different application possibilities are presented, and the costs compared with isolator systems.

As a technology of the future, process-integrated containment is presented using the example of a fluid bed granulator. This method offers many advantages but is not yet used in routine production.

Finally, the planning and design of a containment plant is presented using a case study for the production of active ingredients. During the planning phase, attention should also be paid to possible weak points that could later lead to deficiencies in operation. This concerns the change of filters, cleaning, maintenance and servicing, for example. (Richard Denk)

Chapter 13 Packaging

13.B Packaging process

Packaging plays an important role for the medicinal product: it protects it from external influences during storage and transport, prevents unauthorised access or manipulation, and carries important information for the patient. The packaging thus makes a significant contribution to drug safety.

Depending on the dosage form (solid, liquid, semi-solid), different primary packaging materials are used, such as blisters, screw-top jars, bottles and tubes. The processes for packaging or filling solid, liquid and semi-solid dosage forms also differ.

The packaging process consists of several steps: Bulk goods and packaging material are provided; the packaging line is set up and released. The aim of line clearance is to avoid mix-ups. For line clearance, all control functions are also checked. The packaging process begins after a successful initial sample inspection. During packaging, inprocess controls together with the online control equipment, whose functions are regularly checked, guarantee the product quality. After completion of the packaging order, reconciliation is carried out.

The requirements for labelling pharmaceuticals must always be adapted to the country requirements. These range from simple printing of the batch code and expiry date (minimum requirement according to Directive 2001/83/EC) to complete coding and serialisation for protection against counterfeit medicines. The labelling of the primary and secondary packaging is part of the packaging process.

The reconciliation at the end of a packaging order represents a further quality assurance measure. The quantities of bulk and packaging material used are compared with the yield achieved, taking waste, rejects and residual quantities into account. The aim of the reconciliation is to uncover any discrepancies that could indicate errors in the packaging process.

The packaging also provides protection against counterfeit medicines. According to the so-called „Falsification Directive", since the beginning of 2019, drug packages for the EU must bear at least one tamper-evident seal and an individual identification feature (serialisation number). The measures required for this must be technically integrated into the packaging process.

Like other processes, the packaging process must also be validated. The focus here is on the critical operating parameters during packaging, such as blister sealing pressure and temperature, machine speed, etc. Validation is intended to prove that the process leads to a product of the predefined quality within the specified, qualified operating limits. (Vera Werner, PhD)

GMP Regulations

Chapter F PIC/S Guidelines

F.25 PI 052-1: Inspection of health based exposure limit (HBEL) assessments and use in quality risk management

The aim of the ten-page Aide Memoire is to assist inspectors in the inspection of health-based exposure limits (HBELs). The topics covered are HBEL assessment reports and quality risk assessment for cross-contamination control. The AiM in a checklist format refers to the relevant sections of the GMP guidelines and to Q&A 053-1. The document is of particular interest to all manufacturers who are preparing for an inspection.


F.26 PI 053-1: Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities´

The seven-page Q&A 053-1 originally developed by the EMA, was adopted by PIC/S as a helpful document. With 13 question-answer pairs it supports the PIC/S Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (PI 046) as well as PI052-1: Inspection of health based exposure limit (HBEL) assessments and use in quality risk management.

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