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


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Updates Forecast & History


GMP MANUAL Update No. 17

The content of Update No.17 is outlined below:

GMP in Practice

New Chapters:

  • 13.C Qualification of a servo-controlled blister packaging line
  • 21. Active Pharmaceutical Ingredients (completely new version)

Updated Chapters:

  • 13.B Packaging Process
  • 13.D References
  • 15.B GMP-compliant Documentation

GMP Regulations

New Chapters:

  • Chapter D: CFR and FDA Guidelines
    • D.1.5: 21 CFR Part 4 – Regulation of Combination Products
    • D.1.6: 21 CFR Part 600 – Biological Products: General
    • D.1.7: 21 CFR Part 606 – cGMP for Blood and Blood Components
  • Chapter F: PIC/S Guidelines
    • F.22: PIC/S PE 010-4 – Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments
    • F.23: PIC/S PI 021-2 – GMP Particularities in the Manufacture of Medicinal Products to be Used in Clinical Trials on Human Subjects

Updated Chapters:

  • Chapter C: EU Directives and Guidelines
    • C.4.2: EU GMP Guidelines, Chapter 2 Personnel
    • C.14: Guidelines on Good Distribution Practice of Medicinal Products for Human Use
  • Chapter G: GMP of other Regions
    • G.2.2.7: Canadian Regulations, Annex 14 to the Current Edition of the Good Manufacturing Practices Guidelines – Schedule D Drugs, Human Blood and Blood Components (GUI-0032)
  • Chapter H: Information
    • H.3: Addresses

GMP in Practice

Chapter 13 Packaging

13.B Packaging Process

The chapter starts with an overview of different types of packaging processes for medicinal products and the respective GMP requirements. In the following, the general process flow of a packaging process is outlined and each step discussed in detail. The authors point out that the increased level of automation has led to stricter requirements for the processability of packaging materials. This can be ensured by use of defect evaluation lists during quality control. Product safety on the other hand has to be checked by appropriate
in-process controls. Line clearance, system release and reconciliation are further measures to assure product quality. Last but not least, safety features are of growing importance for the fight against counterfeit medicines. (Dr. C. Gausepohl, R. Brandes)

13.C Qualification of a servo-controlled blister packaging line

Blister packaging is widely used in the pharmaceutical industry because of its many advantages. The qualification of blister packaging lines, however, is a fastidious task due to the complexity and high degree of automation which is typical for modern lines. The author presents a model for a qualification project based on the V-model described in GAMP 5. All steps of this process are explained. A detailed example is given for the functional risk assessment of a blister packaging line, taking into account all elements of a line from the thermoforming machine up to the folding carton ejection. Control systems and supply media are also considered. The chapter rounds up with examples for risk analysis as well as IQ and OQ plans. (R. Röcker)

Chapter 15 Documentation

15.B GMP-compliant Documentation

The regulatory requirements for GMP-compliant documentation are described in Chapter 4 of the EU GMP Guidelines Part I. Nowadays, most documents are created electronically, especially documents of the instruction type. In practice, however, many documents of the record / report type are completed by hand. The aim of GMP-compliant documentation is to ensure  the traceability of a batch history and in doing so contribute significantly to the safety of medicinal products and patients. The basic rule "If it wasn’t documented, it doesn't exist" applies. All documents must be retained in such a way that they are accessible, complete and accurate even after the prescribed retention period. Raw data contains original important information and must therefore be protected against alteration, mix-up and loss. A sample SOP is used to illustrate the key content of a work instruction document on GMP-compliant documentation. (C. Wawretschek)

Chapter 21 Active Pharmaceutical Ingredients

More than 10 years ago, the publication of the ICH Q7A was setting new standards regarding GMP for active substances. In the meantime, active substances have become a focal point of regulatory interest. On the other hand, industry has gained more experience in implementing GMP for APIs. Against this backdrop, we decided to set up a completely new chapter on active substances. The chapter provides information on regulatory requirements, marketing authorization aspects, certificates and auditing. Moreover, the most important active substance classes will be dealt comprehensively. The chapter on chemical active substances which is part of the actual update will be followed by other chapters (biotechnological APIs, herbal APIs etc.)

21.A Introduction

Active substances differ from starting materials, excipients and raw materials in that they have a medicinal, pharmacological or other action that influences the functioning of the body. In addition, there are clear regulatory requirements for manufacturing, testing and marketing active substances. Contrary to the other substances mentioned above, active substances are subjected to comprehensive monitoring by the competent authorities. GMP-compliant manufacturing of active substances has many parallels to medicinal product manufacturing. This becomes evident if the EU GMP Guide, Part I for medicinal products is compared to the EU GMP Guide, Part II for active substances. However, some significant differences have to be considered to keep within the range of official regulations and hence within GMP compliance for active substance manufacturers. (Dr. R. Gnibl)

21.B Regulatory Principles

The ICH Q7 Guideline constitutes the central regulatory work for GMP-compliant manufacturing of active substances worldwide. It has been implemented in Europe as the EU GMP Guide, Part II. More detailed information on the manufacture and testing of biotechnological active substances can be found in Annex 2 of the EU-GMP Guide and in numerous international guidelines. The instructions of the European Pharmacopoeia should also be considered. Registration with the competent national authority is mandatory in Europe for manufacturing, importing and distributing active substances. However, in contrast to medicinal products, no manufacturing or import authorisation requirement for active substances has been implemented in Europe. However, written confirmation has been a requirement since July 2013 for the import of active substances into the European Union from third countries. With regard to the release of active substances for distribution to third parties it should be noted that the prerequisites to be met here have been greatly reduced in comparison to the release of medicinal products. The manufacture, import and distribution of active pharmaceutical ingredients are subject to supervision by the competent national authority. To this end, official GDP or GMP inspection must be conducted in accordance with the guidelines for performing inspections. (Dr. R. Gnibl)

21.C Marketing authorisation documentation for active substances

The quality of the active substances being used must be documented in the marketing authorisation dossier for medicinal products. The applicant may submit the information required for this either in Module 3.2.S of the Common Technical Document (CTD) or in a European Drug Master File (EDMF) or Active Substance Master File (ASMF). It would also be possible to submit a CEP for the active substance (Certificate of Suitability to the Monographs of the European Pharmacopoeia). Thus, the EDMF/ASMF and/or CEP represent different types of standardised ways to document the quality of the active substance being used in a marketing authorisation dossier. Both EDMF/ ASMF as well as CEP represent (only) standardised documentation of active substance production. Therefore, they are basically unsuitable for documenting GMP-compliant manufacturing. (Dr. S. Kettelhoit)

21.D GMP Certificates

An EU-GMP certificate for an active substance manufacturer confirms the GMP-compliant status of a manufacturing site inspected by (EU) health authorities, within the scope of the inspection. Certificates of national health authorities from third countries usually confirm that GMP inspections have been performed in compliance with the fundamental GMP regulations. Whether or not these regulations structures are equivalent to the EU-GMP guidelines must be separately investigated and verified. Therefore, a valid GMP certificate can supply the holder of the manufacturing authorisation with useful information regarding the holder’s obligation to qualify the active substance manufacturer. However, it cannot eliminate the obligation to audit the active substance manufacturer. (Dr. S. Kettelhoit)

21.E Auditing active substance manufacturers

Compliance with special national and/or European regulatory requirements is mandatory for the purchase of medicinal products from third countries such as China or India. Some examples are GMP certification of the country of manufacture, where applicable, import authorization, and mandatory auditing. However, the GMP requirements in China and India for manufacturing active substances are not identical with those of the EU-GMP Guide, Part II in effect in Europe. Another problem is that communication with manufacturers in Asia can be hampered by linguistic and cultural barriers. A GMP audit of manufacturers of active substances places additional burdens on the auditor with regard to the chemical and process-engineering procedures and equipment. The probability of achieving sound audit results increases if the actual audit is prepared and planned carefully. Third-party audits can be used as an alternative to internal audits. When audits are outsourced to providers of third-party audits, these providers must be properly qualified in compliance with the requirements of the organisation’s own QM system and in conformity with Chapter 7 of the EU-GMP Guide. (Dr. S. Kettelhoit)

21.F Chemical Active Substances

Chemical active substances make up the largest group of active substances in terms of quantity and number. The chemical reaction(s) which they undergo during the manufacturing process fundamentally distinguish them from biological/biotechnological and herbal active substances in terms of possible undesired impurities and GMP risks during manufacture. The active substance manufacturer must designate and document the rationale for the starting point from which GMP regulations are applied. Even though the EU GMP Guide Part II is somewhat vague about this, according to the ICH Q11 specification, the latest starting point for observing the GMP regulations nowadays is widely considered to be when a significant structural fragment is incorporated into the structure of the active substance. This means that the purification of a "raw active substance” is no longer accepted by the authorities as the sole step required by GMP. Special risks to be considered in the manufacture of chemical active substances are contamination with organic impurities, inorganic impurities and residual solvents. This must be verified by documented risk management and appropriate risk control strategies in the marketing authorisation documents and through on-site audits. (Dr. S. Kettelhoit)

GMP Regulations

Chapter C: EU Directives and Guidelines

C.4.2 Chapter 2: Personnel

The revised version of Chapter 2 “Personnel” entered into force on February 16, 2014. Changes have been made in order to integrate the principles of a “Pharmaceutical Quality System” as described in the ICH Q10 guideline. The basic principles of the chapter remain unchanged. However, a few new approaches have been added. The revised version of Chapter 2 emphasizes the aspect, that the ultimate responsibility to ensure an effective quality management system is in place and that roles, responsibilities and authorities are defined lies in the hands of the Senior Management. Furthermore, a separate Head of Quality Assurance or Head of Quality Unit may be appointed – depending on the size and organizational structure of a company. Finally, a newly added section on consultants lays down the requirements they have to meet. Consultants should have adequate education, training and experience and their qualifications need to be documented.

C.14 Guidelines on Good Distribution Practice of Medicinal Products for Human Use

A new version of the Guidelines on Good Distribution Practice (GDP) of Medicinal Products was published on November 23, 2013 and entered into force on November 24, 2013. The revised guidelines correct factual mistakes in the subchapters 5.5 and 6.3 and give more explanations on the rationale for the revision. The actual text in 5.5 says that “Medicinal products that are nearing their expiry date/shelf life should be withdrawn immediately from saleable stock”, while medicinal products that are already beyond their expiry date are now excluded. In subchapter 6.3 (ii) the revised text states that "medicinal products returned from a customer (…) should only (formerly always) be returned to saleable stock if they are returned within an acceptable time limit, for example 10 days".

Chapter D: USA: CFR and FDA Regulations

D.1.5 21 CFR Part 4 – Regulation of Combination Products

The FDA has issued the final rule on the cGMP regulations on combination products, which appears in a newly added section to Title 21. 21 CFR Part 4 sets forth the cGMP requirements that apply when drugs, devices, and biological products are combined to create combination products. This new rule also applies to manufacturers of “single-entity” and “co-packaged” combination products. The scope of “manufacturing” activities that fall within the scope of Part 4 include, but are not limited to, repackaging, holding, storage, testing, and designing combination products. The new regulations are based upon the premise that constituent parts of a combination product retain their regulatory status after they are combined. In other words, the manufacturing requirements that apply to each of the constituent parts continue to apply when the parts are combined into the combination product. The new rule became effective on July 22, 2013.

D.1.6 21 CFR Part 600 – Biological Products: General

This part of the Federal Regulations is related to biological products and contains key definitions, establishment standards, establishment inspection requirements and adverse experience reporting requirements.

D.1.7 21 CFR Part 606 – cGMP for Blood and Blood Components

21 CFR Part 606 outlines the cGMP requirements for blood establishments and was designed and is used to ensure that blood and blood components for human use are safe, pure, and effective. The Center for Biologics Evaluation and Research (CBER) also specifies that inspections are conducted to make sure that blood establishments meet process and production controls, equipment regulations, and quality assurance requirements found in 21 CFR Part 211.

Chapter F: PIC/S Guidelines

F.22 PIC/S PE 010-4: PIC/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments

Whereas the PIC/S Guide PE 009 applies to industrial manufacture of distributed medicinal products, the basic requirements presented in this Guide apply to the preparation of medicinal products normally performed by healthcare establishments for direct supply to patients. The Guide is divided into nine main chapters, according to the structure known from the GMP Guide for Industry. The main text is complemented with Annexes specifying the general rules for the preparation of specific types of medicinal products, such as sterile products (Annex 1), non-sterile liquids, creams and ointments (Annex 2) and radiopharmaceuticals (Annex 3). This revised document – which includes the new Annex 3 on radiopharmaceuticals – comes into force on March 1, 2014.

F.23 PIC/S PI 021-2 Aide-mémoire: GMP Particularities in the Manufacture of Medicinal Products to be used in Clinical Trials on Human Subjects

Investigational medicinal products (IMP) must be produced in accordance with the principles and guidelines of GMP for Medicinal Products. The purpose of this document is to provide guidance for GMP inspectors in the evaluation of sites that manufacture, package and label IMPs. It is elaborated to detail the most specific and critical aspects that are necessary to be followed in an inspection with the objective of assuring compliance with the additional requirements specified in PIC/S Annex 13, at the site. Furthermore, the Aide-mémoire aims at maintaining a high standard of quality assurance and uniformity of approach among PIC/S member countries.

Chapter G: GMP of Other Regions

G.2 Canadian Regulations

G.2.2.7 Annex 14 to the Current Edition of the Good Manufacturing Practices Guidelines – Schedule D Drugs, Human Blood and Blood Components (GUI-0032)
The purpose of this document is to provide specific guidance for the application of GMP to blood establishments for human blood and blood components. Only formatting changes were made, but no changes to the content compared to the previous version of Annex 14.


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