HMPWG: guidance on microbial limits

Two important new documents relating to the selection of microbial limits for each stage of the manufacturing process of homeopathic medicinal products are now available on the website of the Homeopathic Medicinal Products Working Group (HMPWG) of the Heads of Medicines Agency: the Points to Consider and the overview of comments HMPWG received during the consultation phase in August 2016.

The Points to Consider document seeks to provide harmonised guidance on the selection of the most appropriate microbial limits from the European Pharmacopoeia (Ph. Eur.) during the different stages of manufacture. Its declared aim is to ensure consistent assessment and mutual recognition of homeopathic medicinal products.

The document includes an explanation and a decision tree for each manufacturing stage: raw materials, homeopathic stocks, homeopathic preparations and finished products. The guidance applies both to products registered under the simplified procedure (Article 14) and to those authorised under Article 16 of Directive 2001/83/EC.

ECHAMP’s evaluation

ECHAMP appreciates HMPWG’s intention to facilitate consistent assessment by the competent authorities by defining harmonised microbial limits and welcomes the fact that some of the comments we submitted during the consultation phase have been accepted.

However we are concerned that requirements should not go beyond the criteria already defined by the European Pharmacopoeia (Ph. Eur.). We believe HMPWG should take into consideration the fact that there are already thousands of registrations of homeopathic medicinal products in the EU based on dossiers, including microbiological testing strategies, already accepted by the competent agencies.

As regards raw material of chemical or mineral origin, homeopathic stocks of botanical origin and stored homeopathic preparations that are not used as finished products, HMPWG foresees the use of the microbial limits established by Ph. Eur. Chapter 5.1.4 (Table 5.1.4-2 - substances for pharmaceutical use) on a ‘non-mandatory’ basis. It allows other limits to be applied if justified.

In its overview of comments received, HMPWG clarifies: ‘… where the MAH applies non-mandatory acceptance criteria, it is understood that these will be accepted by all competent authorities’. This statement is essential in order to ensure harmonisation. However, the Points to Consider do not explain whether limits applied on a ‘non-mandatory’ basis will be accepted by all member states.

If a homeopathic stock or a homeopathic preparation is intended to be the finished product, the acceptance criteria of Ph. Eur. 5.1.4 (Table 5.1.4-1) apply based on the route of administration.

The microbial limits for finished dosage forms are laid down in Ph.Eur. Chapter 5.1.4 (Table 5.1.4-1) and should be applied to the finished product depending on its labelled route of administration.

HMPWG defines aqueous preparations for oral use as preparations containing water, which would mean that all homeopathic ethanol liquid dilutions are to be treated like pure aqueous preparations. Since Ph. Eur. chapter 5.1.4 is applicable to all medicinal products, ECHAMP believes it is EDQM’s role, not that of HMPWG, to make such basic definitions.

Nevertheless, HMPWG further states that data on the bactericidal effects of ethanol are available, and that the content of ethanol can be used to decide whether to apply the microbial limits for non-aqueous or those for aqueous preparations. If the preparation contains ethanol, it must be shown that the content of ethanol has a preservative effect. ECHAMP regrets that HMPWG has missed the opportunity to define, once and for all, the content of ethanol from which the microbial limits for non-aqueous preparations can be applied. The preservative effect of a homeopathic finished product depends on the content of ethanol independently of the company specific product composition. Now, like in the past, it is up to the applicants to deal with the existing different interpretations of the competent agencies. On this point, the main goal of the Points to Consider, which is to achieve a harmonised approach across Europe, cannot be reached.