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LIVE WEBINAR - A better understanding of gelatin cross-linking

With deep knowledge in gelatin formulation and an impressive scientific expertise in softgel technologies, Procaps brings to you a live webinar that will give you an overview on gelatin properties. We will discuss characteristics of gelatin that are not normally taken into account but that can affect physicochemical properties of gelatin related to dissolution or stickiness. Emphasis will be given to the different Critical Quality Attributes that should be evaluated as part of the QbD strategy during the development of drug products containing gelatin, as well as product examples and applications in Softgels and related technologies developed by Procaps. 





Q&A

 1.                       One must control the traces of Formaldehyde in all excipients to prevent cross linking?
Yes. Not just formaldehyde but any potential aldehydes, since they are the main promoters of cross-linking. Additionally, other impurities like peroxides and some metals are also related to these phenomena.
Question made by: Arun Kulkarni, Pharmaxgroup, Inc.
 
2.      First of all, I want to thank you for the invitation.
I had problems to have connection but the seminar is working so far? I'm interested to learn how to control de cross linking in practice
and the regulatory aspects is necessary to defend this thesis.

Thank you first of all for attending our webinar, your question is quite specific but here are some tips for controlling it:
a)     Control aldehydes in your ingredients. Not just the API but the excipients, packaging components, etc.
b)     Check the gelatin raw material you are using, not all types of gelatin apply for all products. Maybe by knowing better your application I can provide you better recommendations. Feel free to contact me at Softigel@procaps.com.co
c)      Check if by using enzymes the problem is solved. See if the enzyme that you are using has significant activity at the dissolution conditions (especially pH and surfactant, if any).
Question made by: Vagner Sena, Gelita
 
3.      Will the in vitro testing (similarity Comparative Dissolution Testing in 3 pH with pepsin and pancreatin) also describe the in vivo testing (BE study)?
Not necessarily. In some cases, two products fail even using enzymes and they are bioequivalent. The ability of a method to establish IVIVC depends on other factors different than the presence of enzymes. However, passing the 3 pHs with the right enzymes, that proves that you have cross-linking but not necessarily that the two products behave similar in vivo.
Question made by: Ni Luh Gede Aryani, Darya
 
4.      Does the gel shell moisture content influence self-crosslinking? What is the min. dryness that can be achieved to avoid self-crosslinking?
In my experience, the answer is yes…but it is not the root cause but it accelerates the rate of reaction. The limit for shell and fill depend on your specific product. Be careful, because drying too much can promote other problems like brittleness or leakers.
Normally, the % of water in the dried shell (by LOD) should be between 5-10%. But again, this is product specific.
Question made by: Marijo Clark, Pharmavite LLC
 
5.        What wavelength of light is the most detrimental or causes self-crosslinking?
Visible or UV can promote but specially UV. However, the action of light is especially important in high humid conditions
Question made by: Marijo Clark, Pharmavite LLC
  
6.        What are the temperatures and RH ranges time at temp/rh that starts the crosslinking process?
Cross-linking is promoted by T and RH, the difference is the rate: lower rate at lower temperatures and especially lower RH. I have seen products that fail al accelerated conditions (40°V/75%RH) after 6 months, but pass 24 months at CRT conditions.
Question made by: Marijo Clark, Pharmavite LLC
 
7.         What method was used to determine mv profiles?
GPC with RI/UV detection.
Question made by: Marijo Clark, Pharmavite LLC
 
8.        What was the initial aldehyde content of the PEG used in the..?
Less than 10 ppm as formaldehyde.
Question made by: Marijo Clark, Pharmavite LLC
 
9.        What is the min. RH level that needs to be avoided? Is the linking only RH driven or a temp/RH?
Cross-linking is promoted by T and RH, the difference is the rate: lower rate at lower temperatures and especially lower RH. I have seen product that fail al accelerated conditions (40°V/75%RH) after 6 months, but passes 24 months at CRT conditions.
Question made by: Marijo Clark, Pharmavite LLC
 
10.     What is the hardness specification you recommend for soft gelatin capsule related to the good dissolution performance?
Dissolution failures occur, if there is cross-liking, with hard or soft capsules. This is not the best parameter to predict cross-linking.
Question made by: Ni Luh Gede Aryani, Darya
 
11.       Does the crosslinking affect in same way for hard gelatin capsules?
Not at all… it is much worst for soft capsules. The reasons? SGCs use more gelatin, more water and more plasticizer…all that contributes to promote cross-linking.
Question made by: Harshada Sant, Tara innovations
 
12.      Which is better type a or b?
Depends on your specific application. I can recommend avoiding potential interactions. For example, for acids compounds try to use acid gelatin. This is not a general rule, but if possible, is recommendable.
Question made by: Arvind Bhalerao, Orit Laboratories LLC
 
13.      Do you see differences between acid hide or acid bone gelatins?
Yes, but it does not mean that one of them is better always. Again, it is product specific.
Question made by: John Prusis, GlaxoSmithKline
 
14.     Can cross linking be reduced/avoided by using sorbitol as the plasticizer in the shell?
In my experience, it can be reduced by avoiding excess of any plasticizer, not specifically sorbitol.
Question made by: Praveen Saligram, SPI Pharma
 
15.      What is the acceptable level of aldehyde in the PEG?
I recommend using USP method, NMT 10 ppm. Be careful of the storage conditions, since aldehydes increase through PEG shelf life, especially in heat/humid and in contact with oxygen.
Question made by: Manoj Maniar, Onconova
 
16.     Can citric acid retard the crosslinking?
Yes, not alone and combined with glycine. Citric acid works as a scavenger for COOH groups of some amino acids that crosslink.
Question made by: Ni Luh Gede Aryani, Darya
 
17.      can you formulate the gelatin during manufacturing by adding excipients that reduce cross linking or would that be bad for the gelatin capsule formation
Yes, but the impact on gelatin depends on the actual excipients you pretend to use. For example, citric acid and glycine have lower impact on gelatin mass properties that could affect encapsulation or drying.
Question made by: Ehab Hamed , Cubist
 
18.     ¿Cómo afecta + o - el proceso de manufactura de la gelatina en planta?
Solo puedo decirte que sí afecta. Hay cierto rango de temperatura y vacío ideal para preparar tu masa de gelatina. Por debajo de ese rango, quedan muchos agregados de gelatina, y por encima, es menos crítico para el cross-linking pero puede afectar la viscosidad y por lo tanto afectar encapsulado y sealing.
Question made by: Ricardo Mercado, Procaps
 
19.      How do you control migration of the vitamin C to the shell?
Pay attention to: plasticizer (type and amount); Drying and residual moisture; Vitamin C source.
Question made by: Ella Elena Braga, Pfizer Inc (Phils)
 
20.    With respect to the effect of aldehydes on cross-linking; which one is better - PEG 200, 300 or 400?
Normally, lower MW of PEG means higher aldehydes…at the same conditions. We recommend 600 or if not possible, then 400. If you need to use lower MWs, pay attention not just to the level of cross-linking but also to the potential migration phenomena between fill and shell…check weight variation during storage.
Question made by: Manoj Maniar, Onconova
 
21.      According to your experience, what is the maximum time of useful life for these capsules?
If you mean regarding no dissolution failures due to cross-linking, if either HGCs or SGCs are well formulated, could be until 4 or 5 years at 25°C/60%RH. But this is product specific.
Question made by: NARDA DELGADO, Laboratorios Rowe