PIC/S PE 009-16 update, Part 1 – changes to Annex 13

FDA light touch on medical devices for patient self monitoring

PIC/S PE 009-16 update, Part 1 – changes to Annex 13

Historically, the PIC/S GMP Guide has chapters and annexes revised, aligned and corrected to close the gap between the international GMP guidelines and to further develop and harmonise GMP standards. PIC/S PE 009-16 (or version 16) of the Guide, recently entered into force on the 1st 2022, and includes changes to Annex 13 “Manufacture of Investigative Medicinal Products” and the inclusion of Annex 16 “Certification by the Authorised Person and Batch Release.”

Starting from this point, is it up to each member or non-member authorities of PIC/S to adapt the new annexes into their own GMP Guides.

Because we have a lot to cover, this blog will be a 2-part series. This blog (Part 1) covers Annex 13, while Part 2 covers Annex 16.

Changes to Annex 13 : Manufacture of Investigative Medicinal Products

The changes to Annex 13 were implemented based on EC Regulation No. 536/2014 on Clinical Trials which replaces EU Annex 13. As a general overview, I find the changes to Annex 13 positive; it has a better structure, is less ambiguous with its requirements, and is also more consistent with conventional good manufacturing practice principles.

As an aside – while going through individual chapters, I have noticed there are frequent recommendations for Part 1 or Annexes 1.11, 15 and the new Annex 16 of the PIC/S GMP Guide to be used as guidance.

There are some instances for which the Annex 13 does not apply:

  • Activities performed outside the authorised manufacturer. These activities are not left outside the review, with clear instructions being provided on measures to be taken for specific situations.
  • The reconstitution process of investigational medicinal products is not considered manufacturing (unless subject to national laws).

Now some details of the changes to Annex 13:

IntroductionIt is recognised that, as knowledge of the investigational medicinal product development and process increases, appropriate tools are required to address specific issues or changes experienced along the way. An important change is that the import activities of the investigational medicinal products have been considered in parallel with the manufacturing activities, both type of activities are expected to comply with the applicable laws and requirements. Another change is the requirement for a technical agreement between the sponsor and manufacturer to be in place, and for the manufacturer to be able to apply and comply with good manufacturing practice principles. I cannot stop thinking at a specific phrase used in this version vs. the previous version of the guide: “subjects are not placed at undue risk” vs “subjects are not placed at risk”. I see it as a subtitle recognition of the reality that, due to the development stage of the product, there are extra risks to the trial participating subjects when compared with marketed products, which translates into the necessity to have extra considerations for detecting and controlling these risks (for example, better cooperation between parties involved, specific training, a thorough application of the risk management principles). As an opinion, the emphasis of the annex is on the definition of the investigational medicinal product, which is placed at the beginning of the annex and in the glossary section, and not on what is a non-investigation medicinal product. In this way, possible errors in interpreting the clauses of the annex can be avoided.
Chapter 1: ScopeAs mentioned above, Annex 13 does not apply to specific activities performed outside the authorised manufacturer, however, these activities should ensure the safety of the subject and the reliability and robustness of the data generated during the clinical trial. Activities under review are processes carried out in hospitals, health care centres or clinics (which are not subject to good manufacturing practice), that are performed only by pharmacists or other authorised persons and intended to be used only in hospitals, health centres or clinics taking part in the same clinical trial in the same country. The chapter provides a list of activities considered.
Chapter 2: Pharmaceutical Quality SystemNot only has the ‘Quality System” term been aligned to the current term used for the authorised medicinal products, but the concept of the chapter started to follow the classical good manufacturing practice requirements, for example: • All deviations from pre-defined specifications and instructions must be registered, investigated, with corrective and preventive actions initiated as appropriate; • The integrity of the supply chain and the protection against falsified products must be ensured. To achieve this, Quality Risk Management principles should be applied to suppliers of starting materials during their selection and qualification. Supplier quality must be continuously monitored, , and their status documented and maintained. If the previous version of the guide recommended taking “into account the GMP principles and guidelines applicable to investigational medicinal products”, this version of the guide recommends following Chapter 1 of Part 1 of the PIC/S GMP Guide as guidance.
Sub-chapter 2.1 Product specification fileThe product specification file was re-designed as an element of the Pharmaceutical Quality System, while the previous version of the guide considered the product specification file as an elementary component of the documentation sub-system. Keeping in mind the importance of product specification file (contains all essential reference documents), as part of the chapter’s re-design, new expectations were included for example: • Specific sections of the product specification file should be available at the start of manufacturing of the first batch of the investigational medicinal products for use in a clinical trial; • The manufacturing site should have access to the necessary documentation, including changes, of the product specification file to allow the relevant activities to be performed. • Extra documents are required to be added to the file, for example: o Clinical trial authorisations and amendments o Stability plans and reports o Plans and arrangements for reference and retention samples o Details of the supply chain including manufacturing, packaging, labelling and testing sites.
Chapter 3 PersonnelThe training process is aligned to the process required to be followed for the manufacturing of the authorised medicinal products with Chapter 2 of Part 1 of the PIC/S GMP Guide is recommended as a guideline. The Supply chain comes up again as an important element of the quality system, this time as the requirement for the Authorised Person to have a broad knowledge of the supply chain of the certified finished batch of the investigational medicinal product.
Chapter 4 Premises and EquipmentThe chapter was largely expanded to the application of the quality risk management process, which includes the potency and toxicological evaluation. The QRM principles, as detailed in Chapters 3 and 5 of Part 1 of the PIC/S GMP Guide, are recommended for the assessment and control of the cross-contamination risks presented by the investigational medicinal products manufactured. As part of this exercise, important technical and organisational elements are considered, for example: • Facility and Equipment: design, use and qualification following Annex 15 of the PIC/S GMP Guide. • Personnel and material flow; • Microbiological controls; • Physio-chemical characteristics of the active substance • Process characteristics • Cleaning processes • Analytical capabilities
Chapter 5 DocumentationThe chapter states from the beginning that the generation and control of documentation should be in line with Chapter 4 of Part 1 of the PIC/S GMP Guide. New measures were included, as follows: • Documentation should be consistent with the Product Specification File. • Sponsor’s responsibilities, and if different entity from the manufacturer, manufacturer’s responsibilities for documents retention of the Product Specification File and the Clinical Trial Master File. An agreement should be in place between the sponsor and the manufacturer for the retention of such documents. • Retention periods should be stipulated for the Product Specification File, the Clinical Trial Master File and batch records, unless otherwise specified by the national laws. • The information captured in the Product Specification File’s documents should form the foundation of manufacturing written instructions and reports. • Manufacturing sites should be included in the approval process of instructions including their subsequent changes. • The specification, generation, testing, security, distribution, handling and retention of any randomisation code as well as the code-break mechanism should be described in a procedure and records maintained.
Chapter 6 ProductionThis chapter has significant changes, as follows: • Validation of the manufacturing process, considering the stage of product development, should be performed following Annex 15 of the PIC/S GMP Guide. • Written cleaning procedures and analytical methods should be implemented to verify the cleaning process should be available. • The principles detailed in Annex 1 of the PIC/S GMP Guide should apply to sterile products. • Retention requirements for a reference sample of comparator product, which has been re-packed or over encapsulated for blinding purposes. • Where products are blinded, systems should be in place, which if necessary, include the manufacture’s responsibilities, to ensure that the blind is achieved and maintained. • The information recorded on the product label should comply with any relevant national laws or requirements. However, for cases where no such requirements exist, this chapter recommends elements that should be considered. • Labelling operations should be performed at an authorised manufacturing site. • Re-labelling activities should be performed in the same condition as the re-labelling activities performed for an authorised medicinal product (e.g. line clearance at the start and the end of the activity, trained personnel, reconciliation performed). • The required information that should be recorded on the over label if the expiry date of the product needs to change.
Chapter 7 Quality ControlNew clauses are included which concentrate on: • The manufacturer should establish and maintain a Quality Control System and this system must be independent of production. • Retention period for samples on investigational medicinal products should comply with the relevant national laws or other requirements. • There are exceptional circumstances where samples are not required to be kept in duplicate (e.g. small amounts of a batch are packed for different markets). • For retention samples, photographic records are accepted for storage of information related to the final packaging, if such records provide enough information. Annex 11 of the PIC/S GMP Guide is still applicable. • Samples are not required of the investigational medicinal product: o which is an unblinded comparator in its original packaging and sourced from the authorised supply chain in the country in which the clinical trial occurs. o if the product holds a marketing authorisation granted by the competent authority of the country in which the clinical trial occurs. • Reference samples should be stored under defined conditions and the storage location defined in a technical agreement between the sponsor, manufacturer and the storage site (as applicable). • If the required quantity (to perform all critical quality attributes tests on at least two occasions) is not retained for the reference sample, this should be justified and agreed on with the national competent authority.
Chapter 8 Release of BatchesThis chapter outlines the requirements defined by the new Annex 16 of the PIC/S GMP Guide, however, like the previous chapters, new requirements have been included, for example: • Cleaning records, stability plans and supply chain verification (including manufacturing, packaging, labelling and testing sites) have been included in the documentation required to be assessed by the Authorised Person as part of batch certification and release. • Shared responsibilities between different Authorised Persons performing batch certification and release should be defined in an agreement. • After batch certification, storage and transport conditions should maintain product quality and supply chain security. Where required to support batch certification, these conditions should be certified by the Authorised Person. • When the manufacturer is delegated by the sponsor to perform the regulatory release in addition to certification by the Authorised Person agreements should be in place between the sponsor and the manufacturer.
Chapter 9 Outsourced OperationsThis new chapter recommends Part I, Chapter 7 of the PIC/S GMP Guide to be followed.
Chapter 10 ComplaintsThe chapter was expanded with the requirement to have a written procedure describing actions to be taken when a complaint is received, investigated and assessed, documented and reported, if necessary, to the relevant competent authority. Part I, Chapter 8 of the PIC/S GMP Guide is recommended to be used for complaints received for investigational medicinal products.
Chapter 11 Recalls and ReturnsThe chapter recommends Chapter 8 of the PIC/S GMP Guide to be followed as guideline. Any arrangements between the manufacturer and the sponsor regarding product destruction are required to be described in a protocol and defined in a technical agreement.
GlossaryNew definitions are included, for example for: • Campaign manufacturing • Expiry date • Manufacture and Preparation • Retest date • Regulatory release


Stay tuned for part 2 – changes to Annex 16: Certification by the Authorised Person and Batch Release!


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