A gift of centenarian heparin! The first crude heparin GMP guide is here

Recently, the national group information platform and the China Biochemical Pharmaceutical Industry Association simultaneously released the "Crude Heparin Production Quality Management Guide" (T/CBPIA 0001-2022) group standard drafted by the China Biochemical Pharmaceutical Industry Association, which was implemented from September 15, 2022, and the group standard of "Crude Heparin Production Quality Management Guide" stipulates the general requirements for crude heparin production process, quality management and quality control, filling the gap in the field of domestic crude heparin production quality management guidelines
。

Heparin (Heparin), named because it is found in the liver, is mainly found in the intestinal mucosa, liver, lungs and other tissue cells of pigs, and is glucosan sulfate extracted from the intestinal mucosa of pigs, because of the good anticoagulant effect of heparin, it has become one of the
common drugs in clinical anticoagulation.

Heparin is a legendary biochemical drug
.
The discovery of heparin is full of surprises, and it has been discovered and continuously studied for more than 100 years, and it is a first-line anticoagulant
in clinical practice.
The fine structure and physiological role of heparin have not been fully understood, and the mystery is still preserved, and the milestones of its discovery are summarized as follows:

In 1916, Jay Mclean (1890~1957), a surgeon in Baltimore, USA, participated in the research
of "brain phospholipid coagulation characteristics" carried out by Professor Howell's research group.
The study found that canine liver extract had a significant anticoagulant effect on cats, and at the time, antithrombin was assumed to be the component that can maintain blood flow, which was the first time anticoagulation
was observed in experiments.
This important discovery was published in a research paper on brain phospholipid blood coagulation in June 1916, but later scientists proved that the so-called "anticoagulant" extracted with ether was not heparin, but a lipid stained with heparin
.

In 1922, the real heparin was the product of the water extraction method established by William Henry Howell (1860~1945), professor of physiology at Johns Hopkins University (belonging to crude heparin).

In 1926, heparin was identified as a water-soluble carbohydrate compound, but the name
heparin was still used.
That is to say, the real acquisition of heparin was obtained in 1922, by Professor Howell from the water extracted from the canine liver, and it has been a hundred years
since the discovery of real heparin in 1922.

People in the industry generally divide the heparin industry industry chain into three parts: upstream, midstream and downstream:

This article combines the "Guidelines for Quality Management of Crude Heparin Production" to sort out the concerns of crude heparin production quality supervision and compliance, the main technical content and scope of application are as follows:

1.
Main technical content:

It stipulates the general requirements
for the production process of crude heparin and its quality management, starting material traceability data.

2.
Scope of application:

It is suitable for judging
the conformity of the quality process of crude heparin production.
It is also suitable for effective quality control
by drug marketing authorization holders (hereinafter referred to as MAH) for the process chain of biological APIs (i.
e.
active substances) used in the production of low molecular weight heparin (LMWH) products from starting material acquisition, process intermediate production, to API production.

3.
Standard purchase information:

At present, the standard text of the group is temporarily unsellable to the public, and the original text can be _istranslated="1"> on the national group information platform if you need to view the original text.

4.
What are the requirements for the organization and personnel of crude heparin GMP production?

● 1 organizational structure: clearly stipulate the job responsibilities
of personnel, such as quality, production, materials, engineering equipment and storage and transportation, in the form of documents.

● 3 key personnel: the person in charge of the enterprise, the person in charge of production management, and the person in charge of quality management should have corresponding professional knowledge and work experience
.
The person in charge of production management and the person in charge of quality management have some special concerns with the current version of GMP (2010 version), which is compared to the following table:

5.
What are the requirements for supply chain management of crude heparin GMP production?

1) Establish documents to prove the traceability of the supply chain, and sign a quality agreement: clarify the quality responsibilities of each participant in the supply chain, ensure the correct receipt, storage, distribution, use and shipment of materials, and prevent pollution, cross-contamination, confusion and errors
.

2) Formulate material supplier quality audit management procedures and establish supplier management files: conduct on-site quality audits of suppliers (if necessary).

3) Formulate pig small intestine collection management procedures: the content at least includes collection methods and precautions, packaging requirements, storage temperature requirements, etc
.

4) Formulate pig small intestine transportation management regulations: pig small intestine is generally used in cold chain transportation or other appropriate methods, transport vehicles should be exclusive, ruminants should not be transported, and refrigerated trucks should be comprehensively disinfected before and after transportation
.

5) Formulate pig small intestine acceptance management procedures and acceptance standards: the acceptance content at least includes: the name of the supplier, the number of pig small intestines, the animal quarantine certification documents of the batch of pig small intestines, etc
.
It is strictly forbidden to deteriorate, rot, destroy, adulterate with other animal gastrums
, etc.
into storage.

6) Formulate the management system of auxiliary materials and packaging materials: production auxiliary materials, such as casing salt, alkaline protease, sodium hydroxide, etc.
, should be placed
in separate areas according to the storage conditions of materials.

7) Formulate quality standards for auxiliary materials and packaging materials: and clarify that they can only be used for production after passing the inspection, and auxiliary materials that exceed the validity period shall not be used for production
.

6.
What are the requirements for the production management of crude heparin GMP production?

1) The production of crude heparin shall be operated in accordance with the approved process regulations and operating procedures and have relevant records to ensure that the product meets the specified quality standards
.
Since crude heparin registration approval, process starting materials can be sourced from pig intestinal mucosa or process intermediates
from different suppliers.
Companies should consider using different sources of starting materials or process intermediates and/or different production processes in the initial production steps, demonstrating in advance that similar crude heparin is consistently available
in terms of relevant quality attributes.

2) Formulate product production batch management procedures: The division of production batches should be able to ensure the uniformity
of product quality and characteristics of the same batch.

3) Formulate management procedures for compiling product batch numbers and determining production dates: each batch of products should prepare a unique batch number, and the production date of the final sales batch should be the production date of the earliest production batch in the mixed batch, and the product packaging date should not be used as the production date
.

4) This guide encourages enterprises to evaluate the equivalence of crude heparin with product MAH and establish a relevant detection system, and the necessary research content to prove the similarity of crude heparin sodium can consider the following factors:

● Determine the quality properties of crude heparin according to the complexity of multi-source porcine small intestinal mucosa or process intermediates;

● Quality comparison
of intermediates from different sources produced by different production processes.
If the critical properties of an intermediate stage cannot be determined, the mass properties of the material can be tested
at a later stage in the production process.

● For the difference in the quality of intermediates from different sources in different production processes, enterprises should explain the list of additional purification or extraction steps, process conditions, intermediates, materials and equipment
.

● Whether the quality of the intermediates obtained through different production processes is acceptable, the enterprise should verify and confirm the production process of low molecular weight heparin (LMWH) APIs through MAH, such as the initial processing steps or the use of different intermediates can produce quality equivalent APIs, then the use of intermediates obtained by different production processes in the production process of low molecular weight heparin (LMWH) APIs is acceptable
.
MAH can be studied and demonstrated
in terms of low molecular weight heparin (LMWH) API quality (e.
g.
, product uniformity) and the safety and efficacy of formulation products.

● When different intermediates are introduced in the production process, the storage time and conditions
of the process intermediates should be determined according to the stability data.

● When the viral safety of MAH low molecular weight heparin (LMWH) APIs mainly or only depends on the virus inactivation of intermediates from different sources or the removal ability of production process steps, enterprises should study, verify the crude heparin virus inactivation process and carry out quality control
.

7.
What are the quality control requirements for crude heparin GMP production?

1) The quality of crude heparin shall not be released for use or supply
until it is judged and meets the relevant quality control technical requirements.

2) The quality control of crude heparin should cover the product process chain, and formulate corresponding quality and technical specifications from starting materials, process intermediates to the key control points of crude heparin production; For example, to ensure the traceability of species and prevent the mixing of different animal organs; Pollutant control and virus safety control during the process chain to prevent bioburden overload and harmful microbial contamination; Effectively ensure that the active substance (heparin) is not destroyed and improve the product yield
.

3) Since the identity characteristics of crude heparin active ingredients require not only bioanalytical characterization, but also low molecular weight heparin (LMWH) products manufactured by their downstream processes using in vitro and/or in vivo immune system studies and comparison
with their relevant reference products.

4) The technical requirements for quality control of crude heparin should be based on the key quality attributes of crude heparin, as well as the accumulation of understanding of crude heparin process and the principle of risk assessment, and corresponding quality control strategies and technical requirements should be formulated to ensure the consistency and stability
of production batches.

References

[1] www.
ttbz.
org.
cn.
China Biochemical Pharmaceutical Industry Association website and APP literature, etc