USP: Plastic Components and Systems Used in the Manufacturing of Drug Products


Posted on the ECA website on May 24, 2017

The USP General Chapters—Packaging and Distribution Expert Committee proposes two new general chapters to address the qualification of polymeric components used in the manufacture of both pharmaceutical and biopharmaceutical active pharmaceutical ingredients (APIs) and drug products (DPs):

  • Chapter 665 Polymeric Components and Systems Used in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products;
  • Chapter 1665 Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products.

The drafts of these two chapters have been published for public comment in Pharmacopeial Forum (PF) 43(3) [May–Jun. 2017]. Deadline for comments is July 31, 2017.

Chapter 665 was initially published as Plastic Components and Systems Used in Pharmaceutical Manufacturing 661.3  in PF 42(3) [May–June 2016]. The current proposals take into account comments received on the 661.3 proposal and from the USP Biocompatibility and Material Characterization Workshop held June 20–21, 2016. The chapter number 1665 was previously assigned to a proposed new general chapter Toxicological Safety Assessment of Extractables and Leachables (announced in the stimuli article “USP Plastic Packaging General Chapters: An Overview” in PF 39(6)). However, chapter number 1665 is now assigned to the proposed new general chapter Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products.

Chapter 665 is structured as follows:


3.1 Initial Assessment:

  • Examines whether a polymeric material, component, or system is fit for its intended use (with respect to patient safety) without further characterization.
  • The first and second steps consider whether there is contact between a component and a process stream and whether the process stream that contacts the polymeric material, component, or system is a liquid.
  • The third step considers whether the material, component, or system is used to manufacture an approved and marketed API, DS, or DP. If a material, component, or system has been established to be acceptable, further characterization of the material, component or system is not required, providing this is justified.
  • The last step considers whether the component or system under assessment is equivalent to a component or system that has already been established to be acceptable (a comparator). For example, a component that is used to manufacture an approved drug product could be a comparator for a second, but similar, component used to manufacture a different, but similar, drug product. In order to link a component or system to a comparator, reference is made to Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products(chapter 1665).
  • When a comparator has been established for the component under assessment, then further characterization of the material, component, or system is not required as long as a justification is provided. When a comparator cannot be established, proceed to 3.2 Risk Assessmentto establish the appropriate and necessary level of material and component testing.

3.2 Risk Assessment:

  • The testing of materials and components is driven by the risk that the material or component could be unsuited for its intended use. The greater the risk that the material or component could be unsuited for use, the greater the degree of required testing. Risk assessment is accomplished via application of a Risk Assessment Matrix detailed inPlastic Components and Systems Used to Manufacture Pharmaceutical Drug Products (chapter 1665).
  • The outcome of this assessment establishes three levels of risk: low (level A), moderate (level B), and high (level C). These levels are linked to the test requirements defined in section 4.2.1 and 4.2.2.
  • If a component has been tested according to this chapter and meets the specifications contained in this chapter, the component’s materials of construction are deemed to be compliant with this chapter without having been tested according to (chapter 661.1).
  • If the component meets the plastic class VI requirements according to USP general chapter 88, it is not necessary to test the component according to chapter 87.
    4.1 Plastic Materials Not Addressed in chapter 661.1
    4.2 Cured Polymeric Materials
    4.2.1 Test Methods
    5.1 Test Methods
    5.2 Specifications:
  • Biological Reactivity:
    (Manufacturing components or systems that do not meet the requirements of the relevant biological reactivity tests (chapters 87 and 88, as appropriate) are not suitable as manufacturing components or systems for pharmaceutical and/or biopharmaceutical use);
  • Extractable Metals;
  • Organic Extractables Profile.

Chapter 1665 discusses material characterization and selection and safety qualifications of polymeric components and systems used to manufacture drug products (previously proposed to be incorporated in general chapter 1661 to support the use and understanding of the new general chapter 661.3). The chapter is structured as follows:

    3.1 Discussion
    3.2 Material Characterization and Selection
    3.3 Component Characterization and SelectionCHARACTERIZATION PROCESS
    4.1 Initial Assessment
    4.2 Risk Assessment
    4.2.1 Risk evaluation matrix
    4.2.2 Application of the risk evaluation matrix
    4.2.3 Using the risk evaluation matrix
    4.2.4 Linking risk to characterization methodologies4.3 Establishing the Level of Characterization
    4.3.1 Baseline assessment
    4.3.2 Expanded baseline assessment
    4.3.3 Full testing (extractables profiling)4.4 Standard Extraction Protocol
    4.4.1 Extraction solvents
    4.4.2 Extraction temperature
    4.4.3 Extraction duration
    4.4.4 Accomplishing the extraction
    4.4.5 Non-standard extractions
    4.4.6 Accounting for conditioning and related steps employed in manufacturing4.5 Testing the Extracts and Generating the Extractables Profile
    4.6 Evaluation of the Extractables Profile Established by Implementing the Standard Extraction Protocol5. SAFETY QUALIFICATION
    5.1 General
    5.2 Chemical Safety Qualification
    5.3 Additional Safety QualificationGLOSSARY

Following your registration on the Pharmacopeial Forum website you get access to the complete drafts of general chapters 665 and 1665.

GMP Requirements for Certificates of Analysis (CoA)

This article is from the ECA Academy website – originally published in January 2017.

At times of outsourcing and globalisation, the significance of Certificates of Analysis (CoA) is growing. Ultimately, the user of such certificates has to rely on their accuracy and completeness.

There are CoAs for excipients, APIs, packaging materials and finished products. A closer look at the guidelines shows that there are a few regulatory requirements which are often unknown. Requirements can be found in the following sets of rules:

  • EU GMP Guide Part I (Chapter 4 and Chapter 6)
  • EU GMP Guide Part II – Section 11.4
  • EMA Guideline on batch certification (Internationally harmonised Requirements for Batch Certification)
  • WHO Annex 10 – Model Certificate of Analysis
  • USP General Chapter <1080> Bulk Pharmaceutical Excipients – CoA
  • IPEC CoA Guide for Pharmaceutical Excipients

According to the EU GMP Guide Part I, certificates of analysis provide an overview of test results obtained from a product or a material. This also includes the assessment of compliance with the specification determined.

Section 11.4 of the EU GMP Guide Part II on certificates of analysis requires an authentic certificate of analysis for each batch of an intermediate or API. Among other things, this certificate should contain the following information:

  • Name of the intermediate or API
  • Batch number
  • Release date
  • Expiry date
  • List of the tests performed including acceptance limits
  • Numerical results
  • Dated signature by authorised personnel
  • Name of the company
  • or Name of the laboratory

You can find specific requirements regarding CoAs in these GMP guidelines. This is a difference to other quality guidelines like e.g. ISO 9001, where you don´t have this concretisation.


FDA Adds Device Scenarios to Final GMP Guidance for Combo Products

In the finalized guidance on GMP requirements for combination product manufacturers, the FDA clarified how to comply with certain device requirements with compliance examples for prefilled syringes, drug-coated mesh and drug-eluting stents. This final version reiterates that combination product manufacturers have two options for compliance: satisfy all drug and device GMPs, or implement a streamlined quality system that focuses primarily on one but incorporates elements of the other GMP systems. This guidance details which GMPs are applicable to a product, general methods for how to implement them, key definitions, and how to make post-market changes to a product’s quality system. 

Read the guidance here.

Who is Responsible for Ensuring GMP Compliance?

GMP stamps2

A recent case from Denmark demonstrated that senior management really is responsible for GMP compliance. The Danish Medicines Agency (DKMA) has now taken an action that reinforces  senior management responsibility in a very significant way: they demanded the replacement of the CEO!

It’s important that senior management understand their critical role in implementing a compliant Pharmaceutical Quality System (PQS) and in creating a good quality culture.

Share this with your senior management.

Guideline on Process Validation for Manufacturing of Biotechnology-Derived Active Substances

Are you up to date on process validation requirements for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submissions for the EU?  Process validation is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an active substance or intermediate meeting its predetermined specifications and quality attributes (ICH Q7).

The EMA just published a new guideline that addresses the data requirements for process characterization and verification for submission of a marketing authorization application or variation.

These principles apply to recombinant proteins and recombinant polypeptides, their derivatives, and products of which they are components (e.g. conjugates). This guideline discusses process characterization and process verification requirements.  It also includes points to consider such as evaluation and verification of the upstream and downstream processes, issues related to single use equipment and multiple harvests, reprocessing, hold time, storage, transportation, and multi-facility production.

Download the full guidance here.