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Updates Forecast & History


GMP MANUAL Update No. 21

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


Air cleanliness classes and grades


Barrier systems, isolators and safety cabinets


Hygienic Design in solids handling


Containment in solids handling


Packaging materials (new author)


Coding and serialisation of folding cartons


Outsourced activities


GMP Regulations


Chapter 3 Premises and equipment


Chapter 5 Production


Concept paper on the revision of annex 1 – manufacture of sterile medicinal products


Commission delegated regulation (EU) No 1252/2014 supplementing Directive 2001/83/EC for active substances for medicinal products for human use


EMA: Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities


FDA: Current good manufacturing practice requirements for combination products – Draft guidance


ICH Q3D: Guideline for elemental impurities


ICH Q12: Technical and regulatory considerations for pharmaceutical product lifecycle management – Final concept paper


GMP in Practice

3.C Air cleanliness classes and grades

In its Annex 1, the EU GMP Guide defines air cleanliness grades A–D and the specific requirements for premises dedicated to sterile production. FDA also defines air cleanliness classes in its Guidance for Industry: Sterile drug products produced by aseptic processing. FDA establishes requirements for critical areas and adjacent supporting clean areas. Compliance with the limits for airborne particles and microorganisms is achieved, above all, by appropriate conception of premises and their ventilation and air-conditioning systems. The development of zoning concepts is recommended in order to cover systematically all relevant aspects of contamination controlled facilities. Alarm and action limits together with the required actions and counteractive measures have to be established preventively for coping with situations where the limit values for airborne particles and microorganisms are exceeded. It is recommended to establish air cleanliness requirements not only for sterile facilities, but also for non-sterile production if this is indicated by risk assessment. (Dr. Hans H. Schicht)

3.E Barrier systems, isolators and safety cabinets

Isolators are compact, self-contained devices that provide a barrier between a work process and the external room environment including the operators. They are highly efficient devices for protecting aseptic filling processes against the risk of microbiological contamination. In addition, they also protect personnel against hazards during the processing of highly active substances, especially those in a solid physical state. Other important pharmaceutical applications include the sterility testing of aseptically filled medicinal products including compound preparation. The statutory requirements that apply to isolator technology can be found in Annex 1 of the EU GMP Guidelines, in the FDA guidelines on the manufacturing of sterile drug
products as well as in EN ISO 14644-7. Other barrier systems, such as the different types of Restricted Access Barrier Systems (RABS concepts) are almost equal to isolators with regard to the protection of aseptic filling processes against microbiological hazards. They are much more flexible than isolators when it comes to format and product change-overs. Because of their excellent product and personnel protection, they are mainly used when highly active or highly toxic substances are processed. RABS are often used in contract manufacture because of their flexibility. Every technology has advantages and disadvantages, therefore a decision on which technology to use must always be based on the proposed application. (Dr. Hans H. Schicht)

Together with isolators and RABS, safety cabinets have also been designed to improve the safety of work processes. There are 3 types of safety cabinets available that provide product protection only or both product and personnel protection. Depending on the requirements, clean benches are used for sterility testing, for example, biosafety cabinets when working with microorganisms and cytostatic safety cabinets when preparing CMR substances. The equirements for safety cabinets are outlined in various standards. Regular maintenance is important when using a safety cabinet to ensure the protection of the product and of personnel. (Andreas Nuhn)

4.C Hygienic Design in solids handling

When planning machinery, not only the regulatory and normative requirements, functionality and cost effectiveness must be observed, but the principles of hygienic design also. Hygienic design results in machines with a closed design that have little dead space and are easy to clean. This is particularly important when handling solids. When it comes to hygienic design, it is standard practice to differentiate between product contact and non-product contact components. This affects, for example, the choice of materials and the required surface finish. It is important that hygienic design is taken into consideration as early as possible during the planning phase and that the required design criteria are outlined in the user requirements specification. Important design characteristics for hygienic design are explained using examples of different types of connections, feeding and dosing systems, and cleanroom installations. The principles of hygienic design can also be applied when designing hoists, roller conveyors, scaffolding and racks. (Richard Denk)

4.I Containment in solids handling

Containment plays an important role in the manufacturing of APIs and drug products. It aims primarily at the protection of operators, but the protection of the product is also a significant aspect. Operator protection becomes more and more important, as new drug substances are often highly potent or even hazardous substances, e.g. cytostatics. The author explains the principlesof primary and secondary containment and presents different grading systems for products. After giving a short description of working in a full protective suit – which means the alternative to using containment systems – a comprehensive overview is given on containment systems, container systems, glove box systems, single-use-systems and sampling devices. The chapter rounds up with considerations on containment facility planning, weak points in containment systems and the measurement of limit values.(Richard Denk)

13.A Packaging materials

Packaging materials have more than one single function: they protect the product to ensure that its specification-compliant quality is maintained throughout the lifespan of the product. Another important aspect is clear labelling in the interests of patient safety. There are also requirements with regard to user-friendliness and counterfeit protection, such as child safety and tamper-evident closure. The most important primary packaging materials and their properties and applications are described in this chapter. When selecting the primary packaging materials, it is important to take possible interactions with the medicinal product into account. Secondary packaging materials are used to protect the primary packaging and identify the medicinal product. The labelling content is regulated by the regulatory authorities and is largely part of the approval documents. The wide range of packaging types, materials and dimensions necessitates a high degree of technical processing. The definition and use of uniform standards would lead to a major reduction in costs. On the other hand, the protection against medicinal product counterfeiting requires individual and, at times, costly measures to protect the originality of the medicinal product and make it recognisable to the consumer. (Roland Kleissendorf)

Testing to ensure that the quality of the primary packaging materials complies with the specification is a major challenge for the medicinal product manufacturer because of the range of special methods used. Testing is therefore normally carried out by the packaging materials manufacturer. This requires qualification of the supplier and a contractual agreement. A less rigorous check can then be carried out at the medicinal product manufacturer when the incoming goods are received. The handling of packaging materials involves a large amount of risk because of the danger of mix-up and confusion. These risks can be reduced by standardising all procedures in the areas of storage, labelling and transport and by using qualified personnel. (Dr. Christian Gausepohl)

19.J Coding and serialisation of folding cartons in the pharmaceutical industry

Medicinal products must be safe – one key requirement in this regard is to prevent that counterfeit medicinal products enter the legal supply chain.Coding and serialisation of folding boxes are two methods of protection against counterfeit of medicinal products. Each individual pack is labeled with a unique number that allows traceability over the entire supply chain. In Europe all medicinal products have to be serialised by the year 2018. This is a big challenge for all parties involved. A concept using a 2D matrix code has been proposed by the EFPIA, but in practice, its realization runs into difficulties. The author gives an overview on serialisation schemes that have already been implemented in some European as well as non-European countries. These approaches however differ from the EFPIA model. Given this background, it seems unlikely that a harmonized serialisation concept will become introduced in Europe or even worldwide. (Roland Kleissendorf)

19.K Outsourced activities

Outsourcing is becoming more and more important due to the increasingly stringent quality and safety requirements that apply to medicinal products and the increasing cost pressure in health care. Outsourcing ensures that the contract giver and the contract acceptor can focus on their core competencies. It is useful when special technologies or expensive equipment are required, provides access to third-party expertise and, at the same time, frees up in-house resources. The legal requirements for outsourcing activities are outlined in Directive 2003/94/EC, and Chapter 7 of the EU GMP Guidelines contains additional information. Within the European Union, the content of the directives is incorporated into national law. The authors explain how the collaboration should be managed. As a rule, the responsibility for the outsourced activities remains with the contract giver. For this reason, the selection, qualification and monitoring of service providers must be described in the QA system of the contract giver. Furthermore, the relevant tasks and responsibilities must be documented in a liability limiting agreement. This also includes the sharing of information between the parties. The contract giver is obliged to monitor the quality of the services provided continuously and check the currentness of the contractual agreements in the Product Quality Review. The liability limiting agreement must ensure that all of the activities are assigned to the interested parties in such a way that there are no gaps or overlaps. The handling of changes and deviations requires clearly defined rules. When a service provider is audited for the first time, the focus should be on the QA system and the related general processes. Subsequent audits should be risk-based. An important aspect of an audit is the opportunity to get to know the contract partner personally and create a basis of trust for further cooperation. (Dr. Frank Böttcher, Dr. iur. Ingo Schneider)

GMP Regulations

C.4.3 Chapter 3 Premises and equipment and C.4.5 Chapter 5 Production

On 23 January 2015, the EU has modified the recently revised Chapter 3 and Chapter 5 regarding transitional arrangements for a stepwise introduction of toxicological evaluations for products in multipurpose facilities. This procedure was adapted to align with the coming into effect of the EMA guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (C. 19 of this MANUAL Update) The EMA guideline is now explicitly mentioned in footnote 1 of the new chapters.

C.6.1.1 Concept paper on the revision of annex 1 of the guideline on good manufacturing practice – manufacture of sterile medicinal products

To be adequately prepared for future requirements is essential in the area of GMP. Therefore, we have decided to provide you with this concept paper. The paper was released by the European Medicines Agency (EMA) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The document was last partially reviewed in 2007. Since then there have been changes in technologies and significant changes in GMP following the adoption of the ICH Q9 and ICH Q10 guidelines. According to the EMA, Annex 1 is being reviewed:

  • to facilitate the implementation of the principles in ICH Q9 and Q10,
  • to extend the underlying concepts to include new areas of technology and processing not previously covered, and
  • to clarify areas which have been highlighted as ambiguous due to the age of the document.
C.12.1 Commission delegated regulation (EU) No 1252/2014 supplementing Directive 2001/83/EC of the European Parliament and of the Council with regard to principles and guidelines of good manufacturing practice for active substances for medicinal products for human use

As the title already suggests the regulation lays down the principles and guidelines of GMP for active substances for medicinal products for human use, including active substances intended for export. It has to be seen as a supplement to Directive 2001/83/EG as explicitly required by Article 47 therein. With this implementation the legal framework of GMP principles for APIs for all EU Member States is complete. Part II of the EU GMP Guide provides further in depth details to these principles. The regulation is binding in its entirety and directly applicable in all Member States of the European Union. The regulation has entered into force on 15 December 2014.

C.19 Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

This document was long expected and aims to recommend an approach for deriving a scientifically based threshold value for individual active substances to be applied for risk identification. The amendments to the Chapters 3 and 5 of the EU GMP Guide (C.4.3 and C.4.5) to avoid cross contamination and to use a science and risk-based approach for establishing threshold values for risk identification are taken into consideration. While Active Pharmaceutical Ingredients (APIs) are not discussed in Chapters 3 and 5 of the GMP Guideline, the general principles outlined in the EMA Guideline to derive a threshold value for risk identification can be applied where required. The procedure proposed in this document for determination of health based exposure limits for a residual active substance is based on the method for establishing the so-called Permitted Daily Exposure (PDE). The document will enter into force on 1 June 2015.

D 1.5.1 Draft guidance for industry and FDA staff: Current good manufacturing practice requirements for combination products

In July 2013 FDA’s new GMP regulations for Combination Products came into force as 21 CFR 4. Now the FDA has released a draft guidance which describes and explains the final rule on cGMP requirements for combination products. In this context we consider the draft version of interest to you. The spectrum of this document is widely ranged. It covers, among other topics:

  • Definition of a combination product
  • Overview of 21 CFR 4 also in terms of 21 CFR 210/211 and 21 CFR 820 General considerations for cGMP compliance
  • What do I need to know about the cGMP requirements specified in 21 CFR 4.4(b)?
  • Application of cGMP requirements to specific types of combination products
E.3.D ICH Q3D: Guideline for elemental impurities

This new guidance has been developed to provide a global policy for limiting metal impurities qualitatively and quantitatively in drug products and active ingredients. The existing ICH Q3A Guideline classifies impurities as organic, inorganic, and residual solvents. The Q3A and Q3B Guidelines effectively address the requirements for organic impurities. ICH Q3C was developed to provide clarification of the requirements for residual solvents. The new Q3D Guideline – as logical continuation – provides similar clarification of the requirements for metals, which are included in the ICH inorganic impurities classification. It applies to new finished drug products and new drug products containing existing drug substances. The principles of risk management are applied. Among others, the following topics are addressed:

  • Establishment of PDEs (Permitted Daily Exposure)
  • Classification of elements
  • Potential sources of elemental impurities, their identification and control
  • Elements to be considered in the risk assessment
  • Conversion between PDEs and concentration limits
  • The application of Q3D to existing products is not expected within the next three years.
E.12 ICH Q12: Technical and regulatory considerations for pharmaceutical product lifecycle management – Final concept paper

The concept paper ICH Q12 on lifecycle management is the logical continuation of the ICH Q8-Q11 guidelines. The proposal is expected to tackle the current lack of a harmonised approach on technical and regulatory considerations for lifecycle management. While the concepts in ICH Q8-Q11 provide opportunities for a more science and risk-based approach for assessing changes across the lifecycle, there are still several gaps as the main focus to date lies on early stages of the lifecycle. The intention behind ICH Q12 is to promote innovation and continual improvement and strengthen quality assurance and reliable supply of product. This also includes proactive planning of supply chain adjustments and will allow regulators (assessors and inspectors) to better understand the firms Pharmaceutical Quality Systems for management of post-approval CMC changes. An adoption of a Step 2-document is planned for 2016.

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