ICH Q7 GUIDE - QUESTIONS AND ANSWERS ON GMP FOR ACTIVE PHARMACEUTICAL INGREDIENTS
Since the publication of the ICH Q7 Guideline on GMP for Active Pharmaceutical Ingredients in November 2000 most companies in the ICH regions have implemented the requirements concerning a GMP compliant manufacture of active pharmaceutical ingredients. Thus, the companies had the chance to gain experiences with the practical implementation of these guidelines for 16 years now. But within this period there arose uncertainties as concerns the interpretation of certain provisions. Additionally there was the need to establish the link between the requirements of ICH Q7 and those of the Guidelines ICH Q8, Q9, Q10 and Q11 published later. The ICH expert group has compiled a question and answers document in close cooperation with the Pharmaceutical Inspection Scheme, PIC/S in order to clarify those uncertainties. The document takes up the inconclusive sections of the Guideline to clarify them against the background of the ICH Guidelines that were published after the ICH Q7 Guideline.
The structure of the Q&A document follows the chapters of the Q7 Guideline. The document contains at least one question and answer to each of these chapters - with the exception of chapter 9 "Packaging and identification labelling of APIs and intermediates".
Already in chapter 1 "Introduction - Scope" two important questions are being asked concerning the scope of the Guideline.
"Should GMP according to ICH Q7 be applied for manufacturing steps before the defined 'API starting material' i.e., steps not identified in grey in Table 1?"
"Does ICH Q7 apply to manufacturing steps for the addition of one or several substance(s) to an API (e.g., to stabilise the API)?"
The table in the Q7 Guideline to which the first question relates explains the scopes of application for GMP. The fields identified in grey mark the areas subject to GMP (such as the introduction of the API starting material into the manufacturing process), but the arrow with the inscription "Increasing GMP requirements" suggests that there has to be applied a certain amount of GMP also for the fields not identified in grey. Hence, it is important to answer the question on the manufacture of precursors to the starting material. The clarification reads as follows:
"ICH Q7 does not apply to steps prior to the introduction of the API starting material. However, there is an expectation that an appropriate level of controls suitable for the production of the API starting material should be applied."
The following is the answer to the question on GMP for mixtures: "When a mixture is classified in the regulatory filing as an API which is used in a drug product, ICH Q7 should be applied to the manufacturing of these mixtures." In the following selection of questions and answers taken from some additional chapters of the Q&A document numerous references clarify the content- related connections to other chapters in ICH Q7 and to the other ICH Q Guidelines.
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3. Personnel
"What is the intent of the statement in [ICH Q7, Section 3.12] 'training should be periodically assessed'?"
"In [ICH Q7, Section 3.12], the statement 'training should be periodically assessed' refers to a system to evaluate if personnel remain proficient and competent in their job tasks and responsibilities, and whether more frequent, additional, or new training is needed and recurring training is up to date."
6. Materials Management
"Is it possible to extend the expiry date or retest date of a raw material and what is the acceptable practice to determine how long it may be extended for?"
"Manufacturing and labelling of raw materials for use by API manufacturers is outside the scope of ICH Q7. As such, retest and expiry dates, as defined in ICH Q7, do not strictly apply to raw materials and may be used in a different manner by the raw material supplier. Expiry date, as defined in the glossary of [ICH Q7, Section 20], applies specifically to the API. API manufacturers may re-evaluate [ICH Q7, Section 7.5] and then use a raw material after the 'expiry date' or 'retest date', based on an appropriate scientific and risk-based justification (e.g., understanding of material attributes, testing, and stability). Similar justifications may be used to extend the date by which the material should be re-evaluated. It is the responsibility of the API manufacturer to ensure the raw materials are appropriate for the intended use at the time of use."
9. Storage and Distribution
"What is meant by 'APIs and intermediates can be transferred under quarantine to another unit under the company's control when...' and is this applicable to contract manufacturers?"
"[ICH Q7, Section 10.20] states 'APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company's control when authorised by the quality unit(s) and if appropriate controls and documentation are in place'.
The second sentence in [ICH Q7, Section 10.20] describes transport situations that are not considered distribution. It provides for physical movement (transfer but not release) of quarantined material to another unit. This unit can be on the same site, different site (within the same company), or a contract manufacturer (see final paragraph below).
The goal of transfer under quarantine is to allow transportation and testing in parallel. Material that is transferred under quarantine is not to be used for further processing until all testing and quality review is complete and the material is released by the quality unit as defined in [ICH Q7, Section 2.22].
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Examples of circumstances where transfer under quarantine may be needed include extraordinary supply chain requirement(s) (e.g., short shelflife), and materials with a lengthy timeframe for required test(s) (e.g., some microbiological tests, etc.).
With appropriate oversight as described in [ICH Q10, Section 2.7], including a written agreement as described in [ICH Q7, Section 16.12], and appropriate ongoing controls, a contract manufacturer may be considered a 'unit under the company's control'. There is a joint responsibility by both parties to clearly justify and document the need to transfer the unreleased intermediate or API, and to ensure appropriate control is maintained to prevent use before full release."
15. Contract Manufacturers (including Laboratories)
"Which outsourced activities are covered by ICH Q7?"
"In the context of ICH Q7, contract manufacturing is the outsourced activity. The term 'outsourced activities', as defined and described in [ICH Q10, Section 2.7, Glossary], aligns with the description of 'contract manufacturer' in [ICH Q7, Section 16].
ICH Q7 defines 'manufacture' as 'all operations of receipt of materials, production, packaging, repackaging, labelling, relabeling, quality control, release, storage, and distribution of APIs and related controls.'
Recommendation
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'Related controls' include any activities or services necessary to support production (e.g., maintenance, calibration, etc.). ICH Q7 applies to any activities performed by the original manufacturer or the company that is performing the activity on behalf of the original manufacturer."
The text of the ICH Q&A document offers a valuable guidance to the interpretation of requirements in the ICH Q7 Guideline by means of its concrete information, cross references and examples. The Active Pharmaceutical Ingredients Committee, APIC, nevertheless thought an additional substantiation of the contents of these documents would be necessary and compiled the "ICH Q7 Q&A How to do document" in order to further facilitate the implementation in the daily business.
Note: Participants of next year's ICH Q7 Training Week will receive a copy of The ICH Q7 Q&A How to do Document.
Author:
Dr Gerhard Becker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around analytical and compliance topics.
