EMA GMP Vs US FDA GMP

Good Manufacturing Practices (GMP) are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods, pharmaceutical products, and medical devices.
Most of the countries have their own regulation for GMP. I would like to discuss on how EMA (EU) GMP differ with the US FDA GMP.
After evaluation of the GMP regulatory comparison of both regulatory authorities, I found that compliance with EU GMPs will most likely also ensure compliance with FDA GMPs because EMA are much more specific and detailed in their guidances as compared to the US FDA
EMA GMP vs. US FDA GMP (A general comparison):
1. Cleaning Validation:
EMA: Annex 15,Clause 41-"Test until clean" is not considered an appropriate alternative to cleaning validation.
FDA: 2 Test until clean- For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases (correspondence to EMA, clause 41, but used in rare cases)
2. Personal training:
a. EMA: Chapter 2, clause 2.9- Continuing training should also be given, and its practical effectiveness should be periodically assessed.
No FDA correspondence for periodic assessment
b. EMA: Chapter 2, clause 2.8- The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance and cleaning personnel
No FDA correspondence
3. Sample:
a. FDA uses the term reserve sample while EMA categorize sample into two types- retention and reference sample. EMA has additional guidance for retention sample.
b. There is no EMA correspondence to US FDA 21 CFR 211.176 (penicillin contamination)
4. Internal audits:
FDA does not specifically address the requirement to conduct, or to keep records of, internal quality assurance audits. EMA has a chapter on Self Inspection in their guidance documents (Chapter 9: Self Inspection)
5. Air room classification:
a. FDA classifies air on the basis of 0.5 micron only. EMA classifies air into 0.5 and 5 micron, respectively.
b. FDA provides air classification requirement for “in operation” only. EMA provides air classification for “dynamic” and “in operation”, respectively.
c. ISO 6 classification is defined only in FDA.
d. EMA provides the description of clothing required for each grade of cleanroom.
e. Blow/fill/seal technology- FDA: The classified environment surrounding BFS machinery should generally meet Class 100,000 (ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding room.
EMA: Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used.
f. EMA- For classification purposes in Grade A zones, a minimum sample volume of 1m cubic should be taken per sample location (No FDA correspondence)
6. Outdoor clothing:
EMA Annex 1, Clause 44- Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. (No FDA correspondence)
7. Labeling requirement for Investigational medicinal product (IMP):
EMA requires expiry date in the label of IMP {Annex 13, clause 26(j)}. FDA exempts the requirement of expiry date for IMP, except when the new drug is reconstituted at the time of dispensing. (21 CFR 211.137)
8. Packaging control for tamper-evident packaging:
FDA (21 CFR 211.132) provides regulation for tamper-evident packaging requirements for over-the-counter (OTC) human drug products. (No EMA correspondence).
A detailed information on GMP regulation can be found in EU legislation-Eudralex: Volume 4 of "The rules governing medicinal products in the European Union" containing guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human use and US FDA 21 CFR 210 and 21 CFR 211
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Cleaning in Cleanroom

Cleanroom is required to prevent contamination during manufacturing of a product. The product can be a biologic or a semiconductor. I would like to discuss about the cleaning methods practiced in medicinal product industry.
European regulation (EMA) is specific in some areas, for their requirement in cleaning procedures in GMP areas. For instance, the intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined (EMA correspondence Annex 15, clause 38) Also, disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilized. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use (EMA correspondence Annex 1, clause 62)

On the other hand, US FDA is more general in their regulatory requirement for cleaning procedures in GMP areas. The requirements for US FDA and EMA for cleaning procedures in GMP area are similar, except for sewage and refusal were the US FDA has specifically mentioned it in their regulation (21 CFR 211.50).

There are guidances and recommendations, provided by various organizations and societies, for maintaining the level of cleanliness required in a cleanroom area. I would like to discuss some of the factors that are considered for cleaning a cleanroom.

Generally, five types of cleaning equipment are used in cleaning:
1. Vacuuming (wet or dry) - It is relatively inexpensive and since no cleaning solution is required, there is no contaminants introduced. However, a wet vacuuming is more efficient because of the additional drag force from the liquid helps in removing the particle.
2. Wet wiping (damp mopping or wiping) - Cleanrooms are often cleaned with a mop and a bucket. For efficient cleaning, a 3-bucket system is preferred.
3. Tacky roller and tacky mats- I have seen a lot of companies using tacking mats. Tacky materials remove contaminant by the technique of adhesion method
4. Wiper- Wipers are dampened (not saturated) with a detergent or a disinfectant solution and used in cleanroom to wipe surfaces and remove contamination
5. Squeegees- It is used to clean windows and tacky cleanroom flooring

Cleaning solution used in cleaning cleanroom is selected based on following factors:
1. Non-toxic to people
2. Non-corrosive
3. Non-inflammable or low flash point
4. Fast drying
5. Harmless to cleanroom surfaces
6. Leaves no contamination that is harmful to the product
7. Reasonably priced.
Ideally, you will not find any cleaning solution that satisfies all the above requirements. Use of alcohol is preferred since it acts as a good bactericidal and evaporates immediately, leaving no residue. Generally, phenol and chlorine-based compounds are less preferred in cleaning critical cleanrooms because of its toxicity. However, chlorine-based compounds are used because they can kill spores, which are not killed by other acceptable disinfectants.
The type of cleaning methods that need to be used depends on the type of room to be cleaned. There are three zones in a cleanroom: 1. Critical zone- where the product is exposed to contamination, 2. Main zone- area surrounding the critical zone, 3. Other- changing areas, ancillary areas etc. Stringent cleaning methods should be employed for cleaning critical zone as compared to ancillary areas. The frequency of cleaning the room and time spent for cleaning the room should be determine and validated. The best way for ascertaining the frequency of cleaning is by measuring the surface particle contamination immediately after cleaning and after pre-determined intervals; so as to determine how long it does takes for the particle concentration to reach at an unacceptable limit. Also, the surface contamination sampling area should be the area which is most difficult to clean. There are various test analytical methods available now to measure the particle concentration. Additionally, there are test that are carried out to ascertain that cleaning are carried out appropriately.

Finally, organize all the documents and schedules so that these can be easily reviewed and managed.

Standards for cleaning, decontamination, and surface cleanliness in industries for higher level of cleanliness are documented in various standards and recommendation:
1. ISO standards (14644-5)
2. IEST-RP-CC-018.2
3. VDI 2083

Some good books to read:
1. Cleanroom Technology: Fundamentals of Design, Testing and Operation, 2nd Edition. ISBN: 978-0-470-74806-0
2. Introduction to Contamination Control and Cleanroom Technology. ISBN: 978-3-527-61313-7





Mopclean Image: http://www.springgrovecleanroom.ie/facility.html

Study Design and Analysis Plan for Pharmacoepidemiology Safety Studies

Recently, FDA provided guidance documents on “Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets” The guidance was limited to pharmacoepidemiology safety studies using electronic healthcare data sets and Medical Devices were not within the scope of this guidance.
Though FDA in its guidance has not recommended any particular study design, FDA strongly discourage the use of “one size fits all design.” In “one size fits all design”, the investigator does not address the study question of interest while designing the study. There were suggestions from expertise like Biotechnology Health Organization (BIO) to highlight the importance of conducting preliminary pilot studies and data assessment. This might help the sponsor to understand the study population, determine the sample size, identify confounding variable and define the study outcomes before finalizing the protocol.
To identify the confounders in the study, FDA have stated to use particular methods that addresses the confounding variable. In general, if a confounding variable is not identified, it might cause damage to the internal validity of the experiment. BIO in its response has commented that FDA should clarify on whether validation on confounding variables should also be conducted.
Additionally, the study design should include the dosage information, the GAP therapy involved, and the data source used in the studies.
Regarding analysis plan, FDA mentions to address pre-specify plan while performing preliminary analysis. Also, other methods like the sub groups method and ad hoc analysis, if used should be described. International Society for Pharmacoepidemiology (IPSE) has specifically commented on ad hoc analysis stating that the FDA has not acknowledged the recent controversies surrounding the ad hoc analysis. Also BIO comments that the primary and secondary analysis should be clearly stated. Additionally, FDA has provided guidance on the QA/QC procedures in the construction of analysis data set and analysis of data.
For additional information and guidances on pharmacoepidemiology studies you can get information from ISPE Guidelines on Good Pharmacoepidemiologic Practices and The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidance. There are also ISPE guidelines for Quality Conduct in DatabaseResearch and ISPOR guidance on conducting and reviewing database studies.

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Data Exclusivity for Biologics

Data exclusivity for biologics provides protection to the clinical data of biological product. The innovator company submits the clinical data to the FDA, and the agency ensures that the protection restricts competitors-generic companies- from gaining access to the clinical data; hence avoiding generic companies' attempt to manufacture similar product (biosimilar) and gain profit from its commercialization.
Manufacturer of a biological company invest a lot of time and money in bringing a biological product from its development stage to its commercialization. For instance, on an average, it takes a decade long, and an expense of hundred million dollars for a company in bringing a new biologic to the market. Thus, an appropriate data-exclusivity period will help the manufacturer to reimburse the cost in bringing the product into the market.
Data-exclusivity period motivates research in developing new drugs. If data-exclusivity is ineffective, companies will focus on producing biosimilars, because of the readily available clinical data, and it is less likely that a company will attempt to put an effort in bringing a new drug into the market. If data-exclusivity is effective, the manufacturer tend to keep the cost of biologics relatively high so as to compensate the cost occurred in the drug development. A data-exclusivity encourages research in the healthcare industry; however, it is equally important for an appropriate period of restricting the data to the public. For example, data-exclusivity of 10 years keeps the biologics out of reach for the patients, and lesser period of data-exclusivity hinders drug discovery.
As every innovator companies brings it product to the market at a price that is expensive to the patients; patients would have less access to the biological product. Hence, an effective data protection for biologics is necessary that will support both research and affordability of medicines to the patients.
In US, a data-exclusivity of 5 years and a cost-sharing system will help achieve, both, affordability of drugs and research in biologics. In a cost sharing approach, the generic company who have access to the clinical data, shares the expenses incurred to the innovator company. A cost sharing approach will help the innovator company to reimburse its expense suffered during the developmental process. A short exclusivity period of 5 years will bring biosimilars early in the market; this will create a competition into the market, ultimately resulting to less expensive medicines, hence more accessible to the patients.
Such an approach will bring an advancement in the research of biological product that can be safe and effective in life-threatening diseases like cancer and HIV.

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